Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Bath, P. M. et al. (2018) Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial. Lancet, 391(10123), pp. 850-859. (doi: 10.1016/S0140-6736(17)32849-0) (PMID:29274727) (PMCID:PMC5854459)

Abstract

Background Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. Methods We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. Findings 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001). Interpretation Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice.

• Item Type: Articles
• Additional Information: Funding: National Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation. The TARDIS start-up phase was funded by the British Heart Foundation (grant PG/08/083/25779, April 1, 2009, to Sept 30, 2012). The NIHR HTA programme funded the main phase of this project (10/104/24, Oct 1, 2012, to Sept 30, 2017).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Langhorne, Professor Peter and McAlpine, Dr Christine
• Authors: Bath, P. M., Woodhouse, L. J., Appleton, J. P., Beridze, M., Christensen, H., Dineen, R. A., Duley, L., England, T. J., Flaherty, K., Havard, D., Heptinstall, S., James, M., Krishnan, K., Markus, H. S., Montgomery, A. A., Pocock, S. J., Randall, M., Ranta, A., Robinson, T. G., Scutt, P., Venables, G. S., Sprigg, N., Christensen, L. M., Bentsen, L., Krarup Hansen, C., Thomsen, T. T., Kruuse, C., Jensen, H. H., Hansen, S. S., Petrovic, V., Beridze, N., Kakabadze, N., Kherkheulidze, T., Kakabadze, D., Toidze, I., Lobjanidze, N., Akiashvili, N., Tevdoradze, A., Khizanishvili, N., Tsanava, T., Taylor, R., Iniesta, I., Kok, J., Duignan, J., Funnell, M., Cariga, P., Rodriguez, M., Watson, I. J., Tennant, S., Macleod, M., Furnace, J., Gow, H., Irvine, J., Joyson, A., Nelson, S., Taylor, V., Smith, M., Bellfield, R., Hairsine, B., Davies, R., Dodd, A., Corrigan, J., Doherty, M., Ahmed, A., Denniss, C., Johnson-Holland, S., Kay, K. A., Palau, R. I., Auld, G., Daboo, P., Erande, R., Grimwood, G., Hove, D., Howaniec, L., Redjep, O., Rangasamay, R., Butt, G., Sandler, D., Reddan, J., Stafford, S., McIlmoyle, J., Maguire, S., Murphy, P., Chambers, J., Guthrie, L., Osborn, M., Steele, A., Burn, M., Benford, A., Misra, A., Hilton, D., O'Brien, E., Amis, E., Finlay, S., Mitchell, J., Geraghty, O., Harvey, K., Hazel, B., Mashate, S., Wilding, P., Sajid, M., Ball, M., Gascoyne, R., Sivakumar, R., Wright, A., Chatterjee, K., Booth, S., Eccleson, H., Kelly, C., Leason, S., Perkins, C., Bruce, D., Brown, E., Clayton, S., Garside, M., Rogers, G., Lawrence, E., Mahmood, S., Watchurst, C., Chadha, D., Glover, L., Holford, L., Smith, K., Walstow, D., Williams, R., O'Shea, L., Goodsell, J., Athulathmudali, C., Barbon, E., Namushi, R., Jacob, P., Johnson, L., Morse, D., McGhee, C., Speirs, O., Atkinson, S., Peacocke, A., Langhorne, P., Graham, R., Wright, F., McAlpine, C., Ravindrane, A., Bajoriene, M., Matter, L., Windebank, S., Giallombardo, E., Dellafera, D., Eglinton, C., Wilson, J., Broughton, D., Chapman, K., Dixon, L., Zaidi, M., Ayes, K., Kessell, J., Manawadu, D., Adegbaju, O., Aeron-Thomas, J., Anderson, K., Brigden, A., Cattermole, E., Good, J., Hassan, S., Khoromana, E., Lee-Carbon, L., Marks, K., Mckenzie, E., Sikondari, N., Cooper, M., Whysall, K., Wynter, I., Bamford, J., Hassan, A., Wanklyn, P., Kambafwile, M., Makawa, L., Waugh, D., Veraque, E., Soliman, M., Arif, S., Brown, R., Butler, S., Hewitt, C., Hindle, J., Pusalkar, A., Beadle, H., Chan, K., Siddiqui, M., Dangri, P., Buddha, S., Asokanathan, A., Mistri, A., Eveson, D., Musarrat, K., Manning, L., Anand, S., Christian, P., Khan, S., Patel, C., Sein, M., Banns, J., Gibson, E., Gordon, T., Gruenbeck, Y., Wong, S., Datta, P., Bateman, G., Jackson, L., Needle, A., Duodu, Y., Oliver, R., Padilla-Harris, C., Barber, M., Esson, D., Brodie, F., McInnes, C., Fotherby, K., Butler, D., Morgan, D., Preece, K., Willberry, A., Dent, M., Hammonds, F., Hunt, J., Vernon, C., O'Kane, D., Faola, F., Lai, P., O'Callaghan, J., Smith, C., Price, C., Lakey, R., Riddell, V., Smith, A., Storey, G., Munshi, S., Buck, A., Clarke, J., Gilzeane, N., Godfrey, M., Keshvara, R., Richardson, C., Roffe, J., Ryan, L., Shelton, F., Sunman, W., Tittle, A., Tomlinson, J., Whittamore, K., Wilkes, G., Owusu-Agyei, P., Temple, N., Mangion, D., Hardwick, A., Netherton, K., Nor, A. M., Hyams, B., Norman, S., Persad, N., Ragab, S., Dickson, C., Dube, J., Jinks, E., Knops, K., Wadams, B., Ali, K., Gaylard, J., Spurling, G., Sztriha, L., Ajao, T., Alao, M., Chan, F. K., Webster, P., Howard, P., Dobson, T. J., Hyatt, L., Sims, D., Cunningham, J., Esisi, B., Cassidy, T., Bokhari, M., McClelland, B., Mokoena, B., Gunathilagan, G., Jones, S., Reader, M., Thomas, G., Tilby, S., Findlay, P., Barrett, F., Leslie, F., Ross, S., Shread, I., Okwera, J., Howe, J., Harrington, F., Courtauld, G., Schofield, C., Donnelly, R., Maddula, M., Scott, J., Beavan, J., Muhidden, K., Memon, I., Clarke, M., Hedstrom, A., Mills, L., Hemsley, A., Bowring, A., Boxall, L., Kingwell, H., Keenan, S., Roughan, C., Manoj, A., Cox, P., Fletcher, G., Lopez, P., Emsley, H., Gregary, B., McLoughlin, A., Raj, S., Roffe, C., Abano, N., Barry, A., Butler, A., Carpio, R., Castro, K., Finney, K., Gomm, S., Hiden, J., Grocott, J., Lyjko, S., Maguire, H., Remegoso, A., Sanyal, R., Stevens, S., Natarajan, I., Chembala, J., Muddegowda, G., Warusevitane, A., Blight, A., Balazikova, O., Lawlor, C., Shaw, L., Button, D., Howcroft, D., Lucas, S., Madigan, B., McCann, S., Dixit, A., Barkat, A., Davis, J., Fawcett, M., Finlay, L., Guy, H., Hays, C., Hogg, V., Horsley, E., Hubbuck, C., Pringle, C., Stevenson, C., Storey, K., Thompson, T., Woodward, S., Banerjee, A., Allcock, C., Merotra, S., Douglass, C., Campbell, E., Jarapa, R., Johnes, M., Keaveney, C., Marsden, T., Naing, Z., Perez, J., Shaw, K., Black, T., Anthony, A., Clarke, C., Paterson, J., Deighton, K., Temlett, E., Blank, C., Doyle, C., Duty, S., Gill, K., Harkness, K., Kamara, C., Richards, E., Elfandi, K., Guyler, P., Harman, P., Khuoge, C., Kunhunny, S., Tysoe, S., Moynihan, B., Adedoyin, T., Chopra, N., Dayal, N., Ghatala, R., Jeyaraj, N., Jones, I., Kennedy, F., Kerin, L., Khanom, N., Lewis, S., Maheswaran, S., Montague, L., Niemierko, M., O'Reilly, J., Trippier, S., Watson, F., Wilkinson, P., Young, E., Dizayee, K., Cochrane, H., O'Connell, J., Mokoena, L., Osborne, E., Nair, A., Greig, J., Jenkins, C., Powell, J., Price, F., Chowdhury, M., Brixey, S., Hunt, L., Rands, N., Rose, G., Stoddart, S., Srinivasan, M., Motherwell, N., Shekhar, R., Fuller, T., Lankester, A., Lingwood, P., Rankin, C., Webb, H., Jupp, B., Bell, J., Hann, G., Longland, B., Ovington, C., Bhaskaran, B., Ayres, G., Bailey, C., Bearne, H., Buxton, J., Fitzell, P., Hilaire, C., Kelly, D., Szabo, S., Tomlin, D., Gamble, E., Charles, B., Kumar, R., Fluskey, T., Mellor, Z., Peters, J., Sutton, V., Kenton, A., Martin, I., Nyabadza, S., Ghosh, S., Henry, M., Kumar, B., Bruce, D., Ambulo, C., Crawford, S., Nozedar, T., Platton, M., Cvoro, V., Couser, M., McCormick, K., Wilkinson, D., Javaid, K., Hurdowar, S., Attygalle, T., Sundayi, S., Orugun, O., Crowther, H., Jolly, R., Poultney, U., Azim, A., Krasinska-Chavez, M., White, J., Sengupta, N., Margalef, J., Metiu, M. G., Meenakshisundaram, S., Dealing, S., Hargroves, D., Beranova, E., Cowie, L., Rudenko, H., Thomson, A., Verrion, A., Rashed, K., Board, S., Buckley, C., Hayward, D., Jenkins, K., Keeling, E., Rowland-Axe, R., Vickers, C., Wood, D., Lehman, A., Erande, R., Patel, M., Russell, H., Rehman, H., Forrest, D., and Farren, P.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Lancet
• Publisher: Elsevier
• ISSN: 0140-6736
• ISSN (Online): 1474-547X
• Published Online: 20 December 2017
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Lancet 391(10123):850-859
• Publisher Policy: Reproduced under a Creative Commons license