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1. Targeting Tyrosine Kinases in Ovarian Cancer: Small Molecule Inhibitor and Monoclonal Antibody, Where Are We Now?

Author

Aimee Rendell, Isobel Thomas-Bland, Lee McCuish, Christopher Taylor, Mudra Binju, and Yu Yu

Subjects
ovarian cancer, tyrosine kinases, platinum resistance, recurrent cancers, cancer vaccine, kinase inhibitors, Biology (General), QH301-705.5
Abstract

Ovarian cancer is one of the most lethal gynaecological malignancies worldwide. Despite high success rates following first time treatment, this heterogenous disease is prone to recurrence. Oncogenic activity of receptor tyrosine kinases is believed to drive the progression of ovarian cancer. Here we provide an update on the progress of the therapeutic targeting of receptor tyrosine kinases in ovarian cancer. Broadly, drug classes that inhibit tyrosine kinase/pathways can be classified as small molecule inhibitors, monoclonal antibodies, or immunotherapeutic vaccines. Small molecule inhibitors tested in clinical trials thus far include sorafenib, sunitinib, pazopanib, tivantinib, and erlotinib. Monoclonal antibodies include bevacizumab, cetuximab, pertuzumab, trastuzumab, and seribantumab. While numerous trials have been carried out, the results of monotherapeutic agents have not been satisfactory. For combination with chemotherapy, the monoclonal antibodies appear more effective, though the efficacy is limited by low frequency of target alteration and a lack of useful predictive markers for treatment stratification. There remain critical gaps for the treatment of platinum-resistant ovarian cancers; however, platinum-sensitive tumours may benefit from the combination of tyrosine kinase targeting drugs and PARP inhibitors. Immunotherapeutics such as a peptide B-cell epitope vaccine and plasmid-based DNA vaccine have shown some efficacy both as monotherapeutic agents and in combination therapy, but require further development to validate current findings. In conclusion, the tyrosine kinases remain attractive targets for treating ovarian cancers. Future development will need to consider effective drug combination, frequency of target, and developing predictive biomarker.

Published
2022
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2. Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI):a single-blind randomised controlled trial

Author

Derek J Hausenloy, Rajesh K Kharbanda, Ulla Kristine Møller, Manish Ramlall, Jens Aarøe, Robert Butler, Heerajnarain Bulluck, Tim Clayton, Ali Dana, Matthew Dodd, Thomas Engstrom, Richard Evans, Jens Flensted Lassen, Erika Frischknecht Christensen, José Manuel Garcia-Ruiz, Diana A Gorog, Jakob Hjort, Richard F Houghton, Borja Ibanez, Rosemary Knight, Freddy K Lippert, Jacob T Lønborg, Michael Maeng, Dejan Milasinovic, Ranjit More, Jennifer M Nicholas, Lisette Okkels Jensen, Alexander Perkins, Nebojsa Radovanovic, Roby D Rakhit, Jan Ravkilde, Alisdair D Ryding, Michael R Schmidt, Ingunn Skogstad Riddervold, Henrik Toft Sørensen, Goran Stankovic, Madhusudhan Varma, Ian Webb, Christian Juhl Terkelsen, John P Greenwood, Derek M Yellon, Hans Erik Bøtker, Anders Junker, Anne Kaltoft, Morten Madsen, Evald Høj Christiansen, Lars Jakobsen, Steen Carstensen, Steen Dalby Kristensen, Troels Thim, Karin Møller Pedersen, Mette Tidemand Korsgaard, Allan Iversen, Erik Jørgensen, Francis Joshi, Frants Pedersen, Hans Henrik Tilsted, Karam Alzuhairi, Kari Saunamäki, Lene Holmvang, Ole Ahlehof, Rikke Sørensen, Steffen Helqvist, Bettina Løjmand Mark, Anton Boel Villadsen, Bent Raungaard, Leif Thuesen, Martin Kirk Christiansen, Philip Freeman, Svend Eggert Jensen, Charlotte Schmidt Skov, Ahmed Aziz, Henrik Steen Hansen, Julia Ellert, Karsten Veien, Knud Erik Pedersen, Knud Nørregård Hansen, Ole Ahlehoff, Helle Cappelen, Daniel Wittrock, Poul Anders Hansen, Jens Peter Ankersen, Kim Witting Hedegaard, John Kempel, Henning Kaus, Dennis Erntgaard, Danny Mejsner Pedersen, Matthias Giebner, Troels Martin Hansen Hansen, Mina Radosavljevic-Radovanovic, Maja Prodanovic, Lidija Savic, Marijana Pejic, Dragan Matic, Ana Uscumlic, Ida Subotic, Ratko Lasica, Vladan Vukcevic, Alfonso Suárez, Beatriz Samaniego, César Morís, Eduardo Segovia, Ernesto Hernández, Iñigo Lozano, Isaac Pascual, Jose M. Vegas-Valle, José Rozado, Juan Rondán, Pablo Avanzas, Raquel del Valle, Remigio Padrón, Alfonso García-Castro, Amalia Arango, Ana B. Medina-Cameán, Ana I. Fente, Ana Muriel-Velasco, Ángeles Pomar-Amillo, César L. Roza, César M. Martínez-Fernández, Covadonga Buelga-Díaz, David Fernández-Gonzalo, Elena Fernández, Eloy Díaz-González, Eugenio Martinez-González, Fernando Iglesias-Llaca, Fernando M. Viribay, Francisco J. Fernández-Mallo, Francisco J. Hermosa, Ginés Martínez-Bastida, Javier Goitia-Martín, José L. Vega-Fernández, Jose M. Tresguerres, Juan A. Rodil-Díaz, Lara Villar-Fernández, Lucía Alberdi, Luis Abella-Ovalle, Manuel de la Roz, Marcos Fernández-Carral Fernández-Carral, María C. Naves, María C. Peláez, María D. Fuentes, María García-Alonso, María J. Villanueva, María S. Vinagrero, María Vázquez-Suárez, Marta Martínez-Valle, Marta Nonide, Mónica Pozo-López, Pablo Bernardo-Alba, Pablo Galván-Núñez, Polácido J. Martínez-Pérez, Rafael Castro, Raquel Suárez-Coto, Raquel Suárez-Noriega, Rocío Guinea, Rosa B. Quintana, Sara de Cima, Segundo A. Hedrera, Sonia I. Laca, Susana Llorente-Álvarez, Susana Pascual, Teodorna Cimas, Anthony Mathur, Eleanor McFarlane-Henry, Gerry Leonard, Jessry Veerapen, Mark Westwood, Martina Colicchia, Mary Prossora, Mervyn Andiapen, Saidi Mohiddin, Valentina Lenzi, Jun Chong, Rohin Francis, Amy Pine, Caroline Jamieson-Leadbitter, Debbie Neal, J. Din, Jane McLeod, Josh Roberts, Karin Polokova, Kristel Longman, Lucy Penney, Nicki Lakeman, Nicki Wells, Oliver Hopper, Paul Coward, Peter O'Kane, Ruth Harkins, Samantha Guyatt, Sarah Kennard, Sarah Orr, Stephanie Horler, Steve Morris, Tom Walvin, Tom Snow, Michael Cunnington, Amanda Burd, Anne Gowing, Arvindra Krishnamurthy, Charlotte Harland, Derek Norfolk, Donna Johnstone, Hannah Newman, Helen Reed, James O'Neill, John Greenwood, Josephine Cuxton, Julie Corrigan, Kathryn Somers, Michelle Anderson, Natalie Burtonwood, Petra Bijsterveld, Richard Brogan, Tony Ryan, Vivek Kodoth, Arif Khan, Deepti Sebastian, Diana Gorog, Georgina Boyle, Lucy Shepherd, Mahmood Hamid, Mohamed Farag, Nicholas Spinthakis, Paulina Waitrak, Phillipa De Sousa, Rishma Bhatti, Victoria Oliver, Siobhan Walshe, Toral Odedra, Ying Gue, Rahim Kanji, Alisdair Ryding, Amanda Ratcliffe, Angela Merrick, Carol Horwood, Charlotte Sarti, Clint Maart, Donna Moore, Francesca Dockerty, Karen Baucutt, Louise Pitcher, Mary Ilsley, Millie Clarke, Rachel Germon, Sara Gomes, Thomas Clare, Sunil Nair, Jocasta Staines, Susan Nicholson, Oliver Watkinson, Ian Gallagher, Faye Nelthorpe, Janine Musselwhite, Konrad Grosser, Leah Stimson, Michelle Eaton, Richard Heppell, Sharon Turney, Victoria Horner, Natasha Schumacher, Angela Moon, Paula Mota, Joshua O'Donnell, Abeesh Sadasiva Panicker, Anntoniette Musa, Luke Tapp, Suresh Krishnamoorthy, Valerie Ansell, Danish Ali, Samantha Hyndman, Prithwish Banerjee, Martin Been, Ailie Mackenzie, Andrew McGregor, David Hildick-Smith, Felicity Champney, Fiona Ingoldby, Kirstie Keate, Lorraine Bennett, Nicola Skipper, Sally Gregory, Scott Harfield, Alexandra Mudd, Christopher Wragg, David Barmby, Ever Grech, Ian Hall, Janet Middle, Joann Barker, Joyce Fofie, Julian Gunn, Kay Housley, Laura Cockayne, Louise Weatherlley, Nana Theodorou, Nigel Wheeldon, Pene Fati, Robert F. Storey, James Richardson, Javid Iqbal, Zul Adam, Sarah Brett, Michael Agyemang, Cecilia Tawiah, Kai Hogrefe, Prashanth Raju, Christine Braybrook, Jay Gracey, Molly Waldron, Rachael Holloway, Senem Burunsuzoglu, Sian Sidgwick, Simon Hetherington, Charmaine Beirnes, Olga Fernandez, Nicoleta Lazar, Abigail Knighton, Amrit Rai, Amy Hoare, Jonathan Breeze, Katherine Martin, Michelle Andrews, Sheetal Patale, Amy Bennett, Andrew Smallwood, Elizabeth Radford, James Cotton, Joe Martins, Lauren Wallace, Sarah Milgate, Shahzad Munir, Stella Metherell, Victoria Cottam, Ian Massey, Jane Copestick, Jane Delaney, Jill Wain, Kully Sandhu, Lisa Emery, Charlotte Hall, Chiara Bucciarelli-Ducci, Rissa Besana, Jodie Hussein, Sheila Bell, Abby Gill, Emily Bales, Gary Polwarth, Clare East, Ian Smith, Joana Oliveira, Saji Victor, Sarah Woods, Stephen Hoole, Angelo Ramos, Annaliza Sevillano, Anne Nicholson, Ashley Solieri, Emily Redman, Jean Byrne, Joan Joyce, Joanne Riches, John Davies, Kezia Allen, Louie Saclot, Madelaine Ocampo, Mark Vertue, Natasha Christmas, Raiji Koothoor, Reto Gamma, Wilson Alvares, Stacey Pepper, Barbara Kobson, Christy Reeve, Iqbal Malik, Emma Chester, Heidi Saunders, Idah Mojela, Joanna Smee, Justin Davies, Nina Davies, Piers Clifford, Priyanthi Dias, Ramandeep Kaur, Silvia Moreira, Yousif Ahmad, Lucy Tomlinson, Clare Pengelley, Amanda Bidle, Sharon Spence, Rasha Al-Lamee, Urmila Phuyal, Hakam Abbass, Tuhina Bose, Rebecca Elliott, Aboo Foundun, Alan Chung, Beth Freestone, Dr Kaeng Lee, Dr Mohamed Elshiekh, George Pulikal, Gurbir Bhatre, James Douglas, Lee Kaeng, Mike Pitt, Richard Watkins, Simrat Gill, Amy Hartley, Andrew Lucking, Berni Moreby, Damaris Darby, Ellie Corps, Georgina Parsons, Gianluigi De Mance, Gregor Fahrai, Jenny Turner, Jeremy Langrish, Lisa Gaughran, Mathias Wolyrum, Mohammed Azkhalil, Rachel Bates, Rachel Given, Rajesh Kharbanda, Rebecca Douthwaite, Steph Lloyd, Stephen Neubauer, Deborah Barker, Anne Suttling, Charlotte Turner, Clare Smith, Colin Longbottom, David Ross, Denise Cunliffe, Emily Cox, Helena Whitehead, Karen Hudson, Leslie Jones, Martin Drew, Nicholas Chant, Peter Haworth, Robert Capel, Rosalynn Austin, Serena Howe, Trevor Smith, Alex Hobson, Philip Strike, Huw Griffiths, Brijesh Anantharam, Pearse Jack, Emma Thornton, Adrian Hodgson, Alan Jennison, Anna McSkeane, Bethany Smith, Caroline Shaw, Chris Leathers, Elissa Armstrong, Gayle Carruthers, Holly Simpson, Jan Smith, Jeremy Hodierne, Julie Kelly, Justin Barclay, Kerry Scott, Lisa Gregson, Louise Buchanan, Louise McCormick, Nicci Kelsall, Rachel Mcarthy, Rebecca Taylor, Rebecca Thompson, Rhidian Shelton, Roger Moore, Sharon Tomlinson, Sunil Thambi, Theresa Cooper, Trevor Oakes, Zakhira Deen, Chris Relph, Scott prentice, Lorna Hall, Angela Dillon, Deborah Meadows, Emma Frank, Helene Markham-Jones, Isobel Thomas, Joanne Gale, Joanne Denman, John O'Connor, Julia Hindle, Karen Jackson-Lawrence, Karen Warner, Kelvin Lee, Robert Upton, Ruth Elston, Sandra Lee, Vinod Venugopal, Amanda Finch, Catherine Fleming, Charlene Whiteside, Chris Pemberton, Conor Wilkinson, Deepa Sebastian, Ella Riedel, Gaia Giuffrida, Gillian Burnett, Helen Spickett, James Glen, Janette Brown, Lauren Thornborough, Lauren Pedley, Maureen Morgan, Natalia Waddington, Oliver Brennan, Rebecca Brady, Stephen Preston, Chris Loder, Ionela Vlad, Julia Laurence, Angelique Smit, Kirsty Dimond, Michelle Hayes, Loveth Paddy, Jacolene Crause, Nadifa Amed, Priya Kaur-Babooa, Roby Rakhit, Tushar Kotecha, Hossam Fayed, Antonis Pavlidis, Bernard Prendergast, Brian Clapp, Divaka Perara, Emma Atkinson, Howard Ellis, Karen Wilson, Kirsty Gibson, Megan Smith, Muhammed Zeeshan Khawaja, Ruth Sanchez-Vidal, Simon Redwood, Sophie Jones, Aoife Tipping, Anu Oommen, Cara Hendry, DR Fazin Fath-Orboubadi, Hannah Phillips, Laurel Kolakaluri, Martin Sherwood, Sarah Mackie, Shilpa Aleti, Thabitha Charles, Liby Roy, Rob Henderson, Rod Stables, Michael Marber, Alan Berry, Andrew Redington, Kristian Thygesen, Henning Rud Andersen, Colin Berry, Andrew Copas, Tom Meade, Henning Kelbæk, Hector Bueno, Paul von Weitzel-Mudersbach, Grethe Andersen, Andrew Ludman, Nick Cruden, Dragan Topic, Zlatko Mehmedbegovic, Jesus Maria de la Hera Galarza, Steven Robertson, Laura Van Dyck, Rebecca Chu, Josenir Astarci, Zahra Jamal, Daniel Hetherington, Lucy Collier, British Heart Foundation, University College London Hospitals NHS Foundation Trust, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden, National Institute for Health Research (Reino Unido), Singapore Ministry of Health, Ministry of Education (Singapur), and Unión Europea. European Cooperation in Science and Technology (COST)

Subjects
Male, Death, Sudden, Cardiac/prevention & control, medicine.medical_treatment, Myocardial Infarction, 030204 cardiovascular system & hematology, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Medicine, ST-SEGMENT ELEVATION, Single-Blind Method, 030212 general & internal medicine, Myocardial infarction, Prospective Studies, Prospective cohort study, Heart Failure/etiology, 11 Medical and Health Sciences, Myocardial Infarction/complications, General Medicine, Middle Aged, RC666, Combined Modality Therapy, LIMB, 3. Good health, Intention to Treat Analysis, Hospitalization, Treatment Outcome, Ischemic Preconditioning, Myocardial, Female, Life Sciences & Biomedicine, Ischemic Preconditioning, Myocardial/methods, medicine.medical_specialty, CONDI-2/ERIC-PPCI Investigators, ISCHEMIA/REPERFUSION INJURY, 03 medical and health sciences, CARDIOPROTECTION, Medicine, General & Internal, Percutaneous Coronary Intervention, General & Internal Medicine, Humans, In patient, Aged, Heart Failure, Intention-to-treat analysis, Science & Technology, ADJUNCT, business.industry, Percutaneous coronary intervention, medicine.disease, United Kingdom, SIZE, Death, Sudden, Cardiac, Emergency medicine, Myocardial infarction complications, Single blind, business, TASK-FORCE
Abstract

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden. The ERIC-PPCI trial was funded by a British Heart Foundation clinical study grant (grant number CS/14/3/31002) and a University College London Hospitals/University College London Biomedical Research Centre clinical research grant. The CONDI-2 trial was funded by Danish Innovation Foundation grants (grant numbers 11-108354 and 11-115818), Novo Nordisk Foundation (grant number NNF13OC0007447), and TrygFonden (grant number 109624). DJH was supported by the British Heart Foundation (grant number FS/10/039/28270), the National Institute for Health Research (NIHR) Biomedical Research Centre at University College London Hospitals, the Duke-National University Singapore Medical School, the Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist-Senior Investigator scheme (grant number NMRC/CSA-SI/0011/2017) and its Collaborative Centre Grant scheme (grant number NMRC/CGAug16C006), and the Singapore Ministry of Education Academic Research Fund Tier 2 (grant number MOE2016-T2-2-021). HEB was supported by the Novo Nordisk Foundation (grant numbers NNF14OC0013337, NNF15OC0016674). RKK is supported by the Oxford NIHR Biomedical Centre. The research was also supported by the NIHR infrastructure at Leeds. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health. This article is based on the work of COST Action EU-CARDIOPROTECTION (CA16225) and supported by COST (European Cooperation in Science and Technology). We thank all study personnel for their invaluable assistance. Sí

Published
2019
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3. Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Author

Rustam Al-Shahi Salman, David P Minks, Dipayan Mitra, Mark A Rodrigues, Priya Bhatnagar, Johann C du Plessis, Yogish Joshi, Martin S Dennis, Gordon D Murray, David E Newby, Peter A G Sandercock, Nikola Sprigg, Jacqueline Stephen, Cathie L M Sudlow, David J Werring, William N Whiteley, Joanna M Wardlaw, Philip M 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 Buchanan, Allan Walker, Aidan Hutchison, Christopher Matthews, Ruth Fraser, Aileen McGrath, Ann Deary, Rosemary Anderson, Pauli Walker, Christian Hansen, Richard Parker, Aryelly Rodriguez, Malcolm Macleod, Thomas Gattringer, Jeb Palmer, Eleni Sakka, Jennifer Adil-Smith, David Minks, Johannes du Plessis, Christine Lerpiniere, Richard O'Brien, Seona Burgess, Gillian Mead, Ruth Paulton, Fergus Doubal, Katrina McCormick, Neil Hunter, Pat Taylor, Ruwan Parakramawansha, Jack Perry, Gordon Blair, Allan MacRaild, Adrian Parry-Jones, Mary Johnes, Stephanie Lee, Kelly Marie Shaw, Ilse Burger, Martin Punter, Andrea Ingham, Jane Perez, Zin Naing, Jordi Morell, Tracy Marsden, Andrea Hall, Sally Marshall, Louise Harrison, Rowilson Jarapa, Edith Wood, Victoria O'Loughlin, David Cohen, Silvie Davies, Kelechi Njoku, Mushiya Mpelembue, Laura Burgess, Radim Licenik, Mmua Ngwako, Nabeela Nisar, Rangah Niranchanan, Tatjana Roganova, Rajaram Bathula, Joseph Devine, Anette David, Anne Oshodi, Fenglin Guo, Emmanuelle Owoyele, Varthi Sukdeo, Robert Ballantine, Mudhar Abbdul-saheb, Angela Chamberlain, Aberami Chandrakumar, Philip Poku, Kirsty Harkness, Catrin Blank, Emma Richards, Ali Ali, Faith Kibutu, Olesia 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, Mark Barber, Derek Esson, Fiona Brodie, Talat Anjum, Mushtaq Wani, Manju Krishnan, Leanne Quinn, Jayne Spencer, Terry 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, Kay Finney, Sue Lyjko, Christine Roffe, Joanne Hiden, Phillip Ferdinand, Vera Cvoro, Khalil Ullah, Nicola Chapman, Mandy Couser, Susan Pound, 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 Appleton, Zhe Law, Oliver Matias, Evangelos Vasileiadis, Cathy Mason, Anthea Parry, Geraldine Landers, Melinda Holden, Basaam Aweid, Khalid Rashed, Linda Balian, Carinna Vickers, Elizabeth Keeling, Sarah Board, Joanna Allison, Clare Buckley, Barbara Williams-Yesson, Joanne Board, Tressy Pitt-Kerby, Alfonso Tanate, Diane 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 Lucas, Kirsty Bond, Bev Maund, Sam Ellis, Paul Mudd, Martin James, Samantha Keenan, Angela Bowring, Julie Cageao, Hayley Kingwell, Caroline Roughan, Anthony Hemsley, Jane Sword, David Strain, Keniesha Miller, Anita Goff, Karin Gupwell, Kevin Thorpe, Hedley Emsley, Shuja Punekar, Alison McLoughlin, Sulaiman Sultan, Bindu Gregory, Sonia Raj, Donna Doyle, Keith Muir, Wilma Smith, Angela Welch, Fiona Moreton, Bharath Kumar Cheripelli, Salwa El Tawil, Dheeraj Kalladka, Xuya Huang, Nicola 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, James Richard Marigold, Fiona 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 Nair, Jill Greig, Pratap Rana, Matthew Robinson, Mohammad Irfan Alam, David Werring, Duncan Wilson, Caroline Watchurst, Maria Brezitski, Luci Crook, Ifan Jones, Azra Banaras, Krishna Patel, Renuka Erande, Caroline Hogan, Isabel Hostettler, Amy Ashton, Shez Feerick, Nina Francia, Nnebuife Oji, Emma Elliott, Talal Al-Mayhani, Martin Dennis, Cathie Sudlow, William Whiteley, Dipankar Dutta, Pauline Brown, Deborah Ward, Fiona Davis, Jennifer Turfrey, Chloe Hughes, Kayleigh Collins, Rehana Bakawala, Susan O'Connell, Jon Glass, David Broughton, Dinesh Tryambake, Lynn Dixon, Kath Chapman, Andrew Young, Adrian Bergin, Andrew Sigsworth, Aravind Manoj, Glyn Fletcher, Paula Lopez, Penelope Cox, Mark Wilkinson, Paul Fitzsimmons, Nikhil Sharma, James Choulerton, Denise Button, Lindsey Dow, Lukuman Gbadamoshi, Joanne Avis, Barbara Madigan, Stephanie McCann, Louise Shaw, Deborah Howcroft, Suzanne Lucas, Andrew Stone, Gillian Cluckie, Caroline Lovelock, Brian Clarke, Neha Chopra, Natasha Clarke, Bhavini Patel, Kate Kennedy, Rebecca Williams, Adrian Blight, Joanna O'Reilly, Chukwuka Orefo, Nilofer Dayal, Rita Ghatala, Temi Adedoyin, Fran Watson, Sarah Trippier, Lillian Choy, Barry Moynihan, Usman Khan, Val Jones, Naomi Jeyaraj, Lourda Kerin, Kamy Thavanesan, Divya Tiwari, Chantel Cox, Anja Ljubez, Laura Tucker, Arshi Iqbal, Caroline Bagnall, Marketa Keltos, Josh Roberts, Becky Jupp, Catherine Ovington, Emily Rogers, Owen David, Jo Bell, Barbara Longland, Gail Hann, Martin Cooper, Mohammad Nasar, Anoja Rajapakse, Inez Wynter, Ijaz Anwar, Helen Skinner, Tarn Nozedar, Damian McArdle, Balakrishna Kumar, Susan 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, Hlaing Thant, Tanya Ingram, Mellor Zoe, Ramesh Durairaj, Melanie Harrison, Sarah Stevenson, Daniela Shackcloth, Jordan Ewing, Victoria Sutton, Mark McCarron, Jacqueline McKee, Mandy Doherty, Ferghal McVerry, Caroline Blair, Mary MacLeod, Janice Irvine, Heather Gow, Jacqueline Furnace, Anu Joyson, Baljit Jagpal, Sarah Ross, Katrina Klaasen, Sandra Nelson, Rebecca Clarke, Nichola Crouch, Beverly MacLennan, Vicky Taylor, Daniel Epstein, Avani Shukla, Vinodh Krishnamurthy, Paul Nicholas, Sammie Qureshi, Adam Webber, Justin Penge, Hawraman Ramadan, Stuart Maguire, Chris Patterson, Ruth Bellfield, Brigid Hairsine, Kelvin Stewart, Michaela Hooley, Outi Quinn, Bella Richard, Sally Moseley, Mandy Edwards, Heidi Lawson, Michelle Tayler, Yogish Pai, Mahesh Dhakal, Bernard Esisi, Sofia Dima, Gemma Marie Smith, Mark Garside, Muhammad Naeem, Vidya Baliga, Gill Rogers, Ellen Brown, David Bruce, Rachel Hayman, Susan Clayton, Ed Gamble, Rebecca Grue, Bethan Charles, Adam Hague, Sujata Blane, Caroline Lambert, Afnan Chaudhry, Thomas 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 Schulz, James Kennedy, Gary Ford, Philip Mathieson, Ian Reckless, Rachel Teal, Giulia Lenti, George Harston, Eoin O'Brien, Joanne Mcgee, Jennifer Mitchell, Elaine Amis, Dominic Handley, Siobhan 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, Ken Fotherby, Debbie Morgan, Farrukh Baig, Karla Jennings-Preece, Donna Butler, Nasar Ahmad, Angela Willberry, Angela Stevens, Baljinder Rai, Prasad Siddegowda, Peter Howard, Lisa Hyatt, Tracey Dobson, David Jarrett, Suheil Ponnambath, Jane Tandy, Yasmin Harrington-Davies, Rebecca Butler, Claire James, Stacey Valentine, Anne Suttling, Peter Langhorne, Gillian 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 Barrie, Danielle Gilmour, Margo Henry, Tom Webb, Linda Cowie, Hannah Rudenko, Shanni McDonald, Natasha Schumacher, Susannah Walker, Tracey Cosier, Anna Verrion, Eva Beranova, Audrey Thomson, Marius Venter, Arindam Kar, Sheila Mashate, Kirsten Harvey, Léjeune Gardener, Vinh Nguyen, Omid Halse, Olivia Geraghty, Beth Hazel, Peter Wilding, Victoria Tilley, Tim Cassidy, Beverley McClelland, Maria Bokhari, Timothy England, Mohana Maddula, Richard Donnelly, Paul Findlay, Ashish Macaden, Ian Shread, Charlotte Barr, Azlisham Mohd Nor, Claire Brown, Nicola Persad, Charlotte Eglinton, Marie Weinling, Benjamin Hyams, Alex Shah, John Baker, Anthony Byrne, Caroline McGhee, Amanda Smart, Claire Copeland, Michael Carpenter, Marion Walker, Richard Davey, Ann Needle, Razik Fathima, Gavin Bateman, Prabal Datta, Andrew Stanners, Linda Jackson, Julie Ball, Michelle Davis, Natalie Atkinson, Michelle Fawcett, Teresa Thompson, Helen Guy, Valerie Hogg, Carole Hays, Stephen Woodward, Mohammad Haque, Eluzai Hakim, Stuart Symonds, Mehran Maanoosi, Jane Herman, Toby Black, Skelton Miriam, Caroline 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, Moore Sally, Isobel Amey, Sophie Newton, Lisa Clayton-Evans, Indra Chadbourn, Rayessa Rayessa, Charde Naylor, Alicia Rodgers, Lisa 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 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 Hussain, Sarah Brown, Miriam Harvey, Jane Homan, Mohammad Khan, Robert Whiting, Leanne Foote, Nicholas Hunt, Helen Durman, Lucy Brotherton, Jayne Foot, Corinne Pawley, Eliza Foster, Alison Whitcher, Kneale Metcalf, Jenny Jagger, Susan 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, Jenny Wilson, Elio Giallombardo, Lucy Sykes, Pradeep Kumar, James Barker, Isabel Huggett, Linda Dunn, Charlotte Culmsee, Philip Thomas, Min Myint, Helen Brew, Nikhil Majmudar, Janice OConnell, George Bunea, Charlotte Fox, Diane Gulliver, Andrew Smith, Betty Mokoena, Naweed Sattar, Ramesh Krishnamurthy, Emily Osborne, David Wilson, Belinda Wroath, Kevin Dynan, Michael Power, Susan Thompson, Victoria Adell, Enoch Orugun, Una Poultney, Rachel Glover, Hannah Crowther, Sarah Thornthwaite, Ivan Wiggam, Aine Wallace, Enda Kerr, Ailsa Fulton, Annemarie Hunter, Suzanne Tauro, Sarah Cuddy, David Mangion, Anne Hardwick, Skarlet Markova, Tara Lawrence, Carmen Constantin, Jo Fletcher, Isobel Thomas, Kerry Pettitt, Lakshmanan Sekaran, Margaret Tate, Kiranjit Bharaj, Rohan Simon, Frances Justin, Sakthivel Sethuraman, Duke Phiri, Niaz Mohammed, Meena Chauhan, Khaled Elfandi, Uzma Khan, David Eveson, Amit Mistri, Lisa Manning, Shagufta Khan, Champa Patel, Mohammed Moqsith, Saira Sattar, Man Yee Lam, Kashif Musarrat, Claire Stephens, Latheef Kalathil, Richard Miller, Maqsud Salehin, Nikki Gautam, Duncan Bailey, Kelly Amor, Julie Meir, Anne Nicolson, Javed Imam, Lisa Wood, Julie White, Mahmud Sajid, George Ghaly, Margaret Ball, Rachel Gascoyne, Harald Proeschel, Simon Sharpe, Sarah Horton, Emily Beaves, Stephanie Jones, Brigitte Yip, Murdina Bell, Linda MacLiver, Brian MacInnes, Don Sims, Jennifer Hurley, Mark Willmot, Claire Sutton, Edward Littleton, Susan Maiden, Rachael Jones, James Cunningham, Carole Green, Michelle Bates, Raj Shekhar, Ellie Gilham, Iman Ahmed, Rachel Crown, Tracy Fuller, Neetish Goorah, Angela Bell, Christine Kelly, Arun Singh, Jamie Walford, Benjamin Tomlinson, Farzana Patel, Stephen Duberley, Ingrid Kane, Chakravarthi Rajkumar, Jane Gaylard, Joanna Breeds, Nicola Gainsborough, Alexandra Pitt-Ford, Emma Barbon, Laura Latter, Philip Thompson, Simon Hervey, Shrivakumar Krishnamoorthy, Joseph Vassallo, Deborah Walter, Helen Cochrane, Meena Srinivasan, Robert Campbell, Denise Donaldson, Nichola Motherwell, Frances Hurford, Indranil Mukherjee, Antony Kenton, Sheila Nyabadza, Irene Martin, Benjamin Hunt, Hardi Hassan, Sarah O'Toole, Bander Dallol, Janet Putterill, Ratneshwari Jha, Rachel Gallifent, Puneet Kakar, Aparna Pusalkar, kelly Chan, Puneet Dangri, Hannah Beadle, Angela Cook, Karen Crabtree, Santhosh Subramonian, Peter Owusu-Agyei, Natalie Temple, Nicola Butterworth-Cowin, Suzanne Ragab, Kerstin Knops, Emma Jinks, Christine Dickson, Laura Gleave, Judith Dube, Jacqui Leggett, Tatiana Garcia, Sissy Ispoglou, Rachel Evans, Sandeep Ankolekar, Anne Hayes, Hlaing Ni, Bithi Rahman, Josette Milligan, Carol Graham, Josin Jose, Breffni Keegan, Jim Kelly, Richard Dewar, James White, Kelly Thomas, Rajkumar, C, University of St Andrews. School of Medicine, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, University of St Andrews. Population and Behavioural Science Division, University of St Andrews. Pure Mathematics, University of St Andrews. School of Psychology and Neuroscience, and University of St Andrews. School of Biology

Subjects
Male, MICROBLEEDS, 030204 cardiovascular system & hematology, AMYLOID ANGIOPATHY, Brain Ischemia, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Secondary Prevention, ACUTE ISCHEMIC-STROKE, Aged, 80 and over, Aspirin, Manchester Cancer Research Centre, medicine.diagnostic_test, Hazard ratio, Brain, Magnetic Resonance Imaging, Superficial siderosis, Cerebral Small Vessel Diseases, Stroke, Treatment Outcome, Female, medicine.drug, CT, medicine.medical_specialty, ANTITHROMBOTIC THERAPY, Clinical Neurology, Neuroimaging, Subgroup analysis, 03 medical and health sciences, Internal medicine, medicine, Journal Article, Humans, Aged, Cerebral Hemorrhage, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, DAS, Magnetic resonance imaging, medicine.disease, SIGNS, ASPIRIN, Neurology (clinical), Tomography, X-Ray Computed, business, SUPERFICIAL SIDEROSIS, Platelet Aggregation Inhibitors, 030217 neurology & neurosurgery
Abstract

Background: Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy.Methods: RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627.Findings: Between May 22, 2013, and May 31, 2018, 537 participants were enrolled, of whom 525 (98%) had intracerebral haemorrhage: 507 (97%) were diagnosed on CT (252 assigned to start antiplatelet therapy and 255 assigned to avoid antiplatelet therapy, of whom one withdrew and was not analysed) and 254 (48%) underwent the required brain MRI protocol (122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group). There were no clinically or statistically significant hazards of antiplatelet therapy on recurrent intracerebral haemorrhage in primary subgroup analyses of cerebral microbleed presence (2 or more) versus absence (0 or 1) (adjusted hazard ratio [HR] 0·30 [95% CI 0·08–1·13] vs 0·77 [0·13–4·61]; pinteraction=0·41), cerebral microbleed number 0–1 versus 2–4 versus 5 or more (HR 0·77 [0·13–4·62] vs 0·32 [0·03–3·66] vs 0·33 [0·07–1·60]; pinteraction=0·75), or cerebral microbleed strictly lobar versus other location (HR 0·52 [0·004–6·79] vs 0·37 [0·09–1·28]; pinteraction=0·85). There was no evidence of heterogeneity in the effects of antiplatelet therapy in any exploratory subgroup analyses (all pinteraction>0·05).Interpretation: Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds. Further randomised trials are needed to replicate these findings and investigate them with greater precision.Funding: British Heart Foundation.

Published
2019
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