Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial
Rustam Al‐Shahi Salman(University of Edinburgh), M. J. S. Dennis, PAG Sandercock, Clm Sudlow, Joanna M. Wardlaw, William Whiteley, Gordon Murray, Jacqueline Stephen, David E. Newby, Nikola Sprigg, DJ Werring, Phil White, Colin Baigent, Daniel Lasserson, Frank Sullivan, Johanna Carrie, Javier Rojas, Shannon Amoils, John Bamford, Jane Armitage, Gabriel Rinkel, Gordon Lowe, Jonathan Emberson, Karen Innes, Lynn Dinsmore, Jonathan Drever, Carol Williams, David Perry, Connor McGill, David L. Buchanan, Allan Walker, Aidan Hutchison, Christopher R. Matthews, Ruth Fraser, Aileen McGrath, Ann Deary, Rosemary Anderson, Pauli Walker, Christian Holm Hansen, Richard Parker, Aryelly Rodríguez, Malcolm Macleod, Thomas Gattringer, Jeb Palmer, Eleni Sakka, Jennifer Adil-Smith, David Minks, Dipayan Mitra, Priya Bhatnagar, Johan du Plessis, Yogish Joshi, Christine Lerpiniere, Richard O’Brien, Seona Burgess, Gillian Mead, Ruth Paulton, Fergus Doubal, Katrina McCormick, Neil Hunter, Pat Taylor, Ruwan Parakramawansha, Jack Perry, Gordon W. Blair, Allan MacRaild, Adrian Parry‐Jones, Mary Johnes, Stephanie J. Lee, Kelly Marie Shaw, Ilse Burger, Martin Punter, Andrea Ingham, Jane Perez, Zin Naing, Jordi Morell, Tracy Marsden, Andrea C. Hall, Sally J. Marshall, Louise Harrison, R. Jarapa, Edith Wood, V. O'Loughlin, David Cohen, Silvie Davies, Kelechi Njoku, Mushiya Mpelembue, Laura Burgess, Radim Líčeník, Mmua Ngwako, Nabeela Nisar, Rangah Niranchanan, Tatjana Roganova, Rajaram Bathula, Joseph E. Devine, Anette David, Anne Oshodi, Fenglin Guo, Emmanuelle Owoyele, Varthi Sukdeo, ROBERT I. W. BALLANTINE, Mudhar Abbdul-saheb, Angela Chamberlain, Aberami Chandrakumar, Philip Poku, Kirsty Harkness, Catrin Blank, Emma Richards, Ali Ali, Faith Kibutu, O. Yu. Balitska, Kathryn Birchall, Pauline Bayliss, Clare Doyle, Kathy Stocks, Arshad Majis, Jo Howe, Christine Kamara, Luke Barron, Ahmad Maatouk, Ralf Lindert, Katy Dakin, Jessica Redgrave, Biju Bhaskaran, Isam Salih, Debs Kelly, Susan Szabo, Dawn Tomlin, Helen Bearne, Jean Buxton, Pauline Fitzell, Georgina Ayres, Afaq Saulat, Kathleen Horan, Joanne Garfield-Smith, Harbens Bhakri, Paul Guyler, Devesh Sinha, Thayalini Loganathan, Amber Siddiqui, Anwer Siddiqui, Lucy Coward, Swapna Kunhunny, Sharon Tysoe, Rajalakshmi Orath Prabakaran, Shyam Kelavkar, Sindhu Rashmi, David Ngo, Kheng Xiong Ng, Nisha Menon, Sweni Shah(University of Edinburgh), Mark Barber, Derek Esson, Fiona Brodie, Talat Anjum, Mushtaq Ahmad Wani, Manju Krishnan, Leanne Quinn, Jayne Spencer, Terry E. Jones, Helen Thompson-Jones, Lynne Dacey, Srikanth Chenna, Sharon Storton, Sarah Thomas, Teresa Beaty, Shelley Treadwell, Caroline Davies, Susan Tucker, Lynda Connor, Peter Slade, Glyn Gainard, Girish Muddegowda, Ranjan Sanyal, Alda Remegoso, Nenette Abano, Chelsea Causley, Racquel Carpio, Stephanie Stevens, Adrian Butler, Resti Varquez, Hayley Denic, Francis Alipio, Andrew Moores, Adrian Barry, Holly Maguire, Jeanette Grocott, K. Finney, Sue Lyjko, Christine Roffe, Joanne Hiden, Phillip Ferdinand, Vera Cvoro, Khalil Ullah, Nicola Chapman, Mandy Couser, Susan Pound, Katrina McCormick, Sean Mcauley, Senthil Raghunathan, Faye Shelton, Amanda Hedstrom, Margi Godfrey, Diane Havard, Amanda Buck, Kailash Krishnan, Nicola Gilzeane, Jack Roffe, Judith Clarke, Katherine Whittamore, Saima Sheikh, Rekha Keshvara, Carla Jordan, Benjamin Jackson, Gwendoline Wilkes, Jason P. Appleton, Zhe Kang Law, Oliver Matias, Evangelos Vasileiadis, Cathy Mason, Anthea Parry, G Landers, Melinda Holden, Basaam Aweid, Khalid Rashed, L. Balian, Carinna Vickers, Elizabeth G. Keeling, Sarah Board, Joanna Allison, C Buckley, Barbara Williams-Yesson, Joanne Board, T Pitt-Kerby, Alfonso Tanate, Diane P. Wood, Manohar Kini, Dinesh Chadha, Deborah Walstow, Rosanna Fong, Robert Luder, Tolu Adesina, Jill Gallagher, Hayley Bridger, Elodie Murali, Maneesh Bhargava, Chloe van Someren, Frances Harrington, Abhijit Mate, Ali James, Gillian Courtauld, Christine Schofield, Katja Adie, Linda F. Lucas, Kirsty Bond, Bev Maund, Sam Ellis, Paul N. Mudd, Martin James, Samantha Keenan, A Bowring, Julie Cageao, Hayley Kingwell, Caroline Roughan, Anthony Hemsley, Jane Sword, W. David Strain, Keniesha Miller, Anita Goff, Karin Gupwell, Kevin E. Thorpe, Hedley Emsley, Shuja Punekar, Alison McLoughlin, Sulaiman Sultan, Bindu Gregory, Sonia Raj, Donna Doyle, Keith W. Muir, W. G. J. Smith, Angela Welch, Fiona Moreton, Bharath Kumar Cheripelli, Salwa El Tawil, Dheeraj Kalladka, Xuya Huang, Nicola C. Day, Sankaranarayanan Ramachandran, Caroline Crosbie, Jennifer Elliot, Tony Rudd, Katherine Marks, Ajay Bhalla, Jonathan Birns, Sagal Kullane, Nic Weir, Christopher Allen, Vanessa Pressly, Pam Crawford, Emma Battersby-Wood, Alex Blades, Shuna Egerton, Ashleigh Walters, Sue Evans, Richard Marigold, Fiona E. Smith, Gabriella Howard, Imogen Gartrell, Simon Smith, Robyn Creeden, Chloe Cox, Cherish Boxall, Jonathan Hewitt, Claire Nott, Procter Sarah, Jessica Whiteman, Steve Buckle, Rebecca Wallace, Rina Mardania, Jane Gray, Claire Triscott, Anand R. Nair, Jill Greig, Pratap Rana, Matthew K. Robinson, Mohammad Irfan Alam, Duncan Wilson, C Watchurst, Maria Brezitski, Luci Crook, Ifan Jones, Azra Banaras, Krishna Patel, Renuka Erande, Caroline Hogan, Isabel C. 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Crawford, Arunkumar Annamalai, Alex Ramshaw, Clare Holmes, Sarah Caine, Mairead Osborn, Emily Dodd, Peter Murphy, Nicola Devitt, Pauline Baker, Amy Steele, Lucy Belle Guthrie, Samantha Clarke, Ahamad Hassan, Dean Waugh, Emelda Veraque, Linetty Makawa, Mary Kambafwile, Marc Randall, Vasileios Papavasileiou, Claire Cullen, Jenny Peters, Thant Hlaing, Tanya Ingram, Mellor Zoe, Ramesh Durairaj, Melanie Harrison, Sarah Stevenson, Daniela Shackcloth, Jordan Ewing, Victoria Sutton, Mark O. McCarron, Jacqueline McKee, Mandy Doherty, Ferghal McVerry, Caroline Blair, Mary Joan MacLeod, Janice Irvine, Heather Gow, Jacqueline Furnace, Anu Joyson, Baljit Jagpal, Sarah J. 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Harrison, Kari Saastamoinen, Dionne Hove, Laura Howaniec, Gemma Grimwood, Ozlem Redjep, Fiona Humphries, Lucia Argandona, Larissa Cuenoud, Esther Erumere, Sageet Amlani, Grace Auld, Afraim Salek‐Haddadi, Ursula G. Schulz, James Kennedy, Gary A. Ford, Philip Mathieson, Ian Reckless, Rachel Teal, Giulia Lenti, George Harston, Eoin O’Brien, Joanne McGee, Jennifer Mitchell, Elaine Amis, Dominic Handley, Siobhán Kelly, George Zachariah, Jobbin Francis, Sarah Crisp, Juliana Sesay, Sarah Finlay, Helen Hayhoe, Niamh Hannon, Tom Hughes, Bethan Morse, Henry de Berker, Emma Tallantyre, Ahmed Osman, Susan White, Stefan Schwarz, Benjamin Jelley, Rajendra Yadava, Khalid Azhar, Julie Reddan, Mirriam Sangombe, Samantha Stafford, K. Fotherby, Debbie Morgan, Farrukh Baig, Karla Jennings-Preece, Donna Butler, Nasar Ahmad, Angela Willberry, Angela Stevens, Baljinder Rai, Prasad Siddegowda, Peter Howard, Afaq Saulat, Lisa Hyatt, Tracey Dobson, David Jarrett, S. Ponnambath, Jane Tandy, Yasmin Harrington-Davies, Rebecca K. Butler, Claire James, Stacey L. Valentine, Anne Suttling, Peter Langhorne, G.R. Kerr, Fiona Wright, Ruth Graham, Christine McAlpine, Mohammad Shahzad Iqbal, Louise Humphreys, Kath Pasco, Olga Balazikova, Ashraf Nasim, Cassilda Peixoto, Louise Gallagher, Shahrzad Shahmehri, Sandip Ghosh, Elizabeth S. Barrie, Danielle Gilmour, Margo Henry, Tom Webb, Linda Cowie, Hannah Rudenko, Shanni McDonald, Natasha Schumacher, Susannah B. Walker, Tracey Cosier, Anna Verrion, Eva Beranová, Audrey Thomson, Marius Venter, Arindam Kar, Sheila Mashate, Kirsten Harvey, Léjeune Gardener, Vinh Nguyen, Omid Halse, Olivia Geraghty, Beth Hazel, Peter Wilding, Victoria Tilley, Bernard Esisi, Tim Cassidy, Beverley McClelland, Maria Bokhari, Timothy J. 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Clarke, Alpha Anthony, Michele Tribbeck, Julie Cronin, Denise Mead, Ruth Fennelly, James McIlmoyle, Christina Dickinson, Carol Jeffs, Sajjad Anwar, Joanne Howard, Kirsty Jones, Saikat Dhar, Caroline Clay, Muhammad Siddiq, Simone Ivatts, Yolanda Baird, Sally Moore, Isobel Amey, Sophie Newton, Lisa Clayton-Evans, Indra Chadbourn, Rayessa Rayessa, Charde Naylor, Alicia Rodgers, Lisa M Wilson, Sarah Wilson, Emma Clarkson, Ruth Davies, Paula Owings, Graeme Sangster, Valerie Gott, Victoria Little, Pauline Weir, Suja Cherian, Deepa Jose, Helen Moroney, Susan Downham, Angela Dodd, Venetia Vettimootal Johnson, Laura Codd, Naomi Robinson, Ashraf Ahmed, Mo Albazzaz, Sharon A. Johnson, Carol Denniss, Mishell Cunningham, Tajammal Zahoor, Timothy Webster, Sandra Leason, Syed Haider, Kausic Chatterjee, Arumugam Nallasivan, Charlotte Perkins, Samantha Seagrave, Colin Jenkins, Fiona Price, Claire Hughes, Lily Mercer, Malik Azhar Hussain, Sarah Brown, Miriam Harvey, Jane Homan, Mohammad Amir Khan, Robert F. Whiting, Leanne Foote, Nicholas Hunt, Helen Durman, Lucy Brotherton, Jayne Foot, Corinne Pawley, Eliza Foster, Alison Whitcher, Kneale Metcalf, Jenny Jagger, Susan A. McDonald, Kelly Waterfield, Patrick Sutton, Naval Shinh, Ajmal Anversha, Garth Ravenhill, Richard Greenwood, Janak Saada, Alison Wiltshire, Rebekah Perfitt, Sreeman Andole, Naveen Gadapa, Karen Dunne, Magdalini Krommyda, Evelyne Burssens, Sam King, Catherine Plewa, Nigel Smyth, J. Wilson, Elio Giallombardo, Charlotte Eglinton, Lucy Sykes, Pradeep Kumar, James L. 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Abstract
BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation.
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