Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies

Duncan Wilson, Gareth Ambler, Keon-Joo Lee, Jae-Sung Lim, Masayuki Shiozawa, Masatoshi Koga, Linxin Li, Caroline Lovelock, Hugues Chabriat, Michael Hennerici, Yuen Kwun Wong, Henry Ka Fung Mak, Luis Prats-Sánchez, Alejandro Martínez-Domeño, Shigeru Inamura, Kazuhisa Yoshifuji, Ethem Murat Arsava, Solveig Horstmann, Jan Purrucker, Bonnie Yin Ka LamAdrian Wong, Young Dae Kim, Tae-Jin Song, Maarten Schrooten, Robin Lemmens, Sebastian Eppinger, Thomas Gattringer, Ender Uysal, Zeynep Tanriverdi, Natan M. Bornstein, Einor Ben Assayag, Hen Hallevi, Jun Tanaka, Hideo Hara, Shelagh B. Coutts, Lisa Hert, Alexandros Polymeris, David J. Seiffge, Philippe Lyrer, Ale Algra, Jaap Kappelle, Rustam Al-Shahi Salman, Hans R. Jäger, Gregory Y. H. Lip, Heinrich P. Mattle, Leonidas D. Panos, Jean-Louis Mas, Laurence Legrand, Christopher Karayiannis, Thanh Phan, Sarah Gunkel, Nicolas Christ, Jill Abrigo, Thomas Leung, Winnie Chu, Francesca Chappell, Stephen Makin, Derek Hayden, David J. Williams, M. Eline Kooi, Dianne H. K. van Dam-Nolen, Carmen Barbato, Simone Browning, Kim Wiegertjes, Anil M. Tuladhar, Noortje Maaijwee, Christine Guevarra, Chathuri Yatawara, Anne-Marie Mendyk, Christine Delmaire, Sebastian Köhler, Robert van Oostenbrugge, Ying Zhou, Chao Xu, Saima Hilal, Bibek Gyanwali, Christopher Chen, Min Lou, Julie Staals, R. gis Bordet, Nagaendran Kandiah, Frank-Erik de Leeuw, Robert Simister, Aad van der Lugt, Peter J. Kelly, Joanna M. Wardlaw, Yannie Soo, Felix Fluri, Velandai Srikanth, David Calvet, Simon Jung, Vincent I. H. Kwa, Stefan T. Engelter, Nils Peters, Eric E. Smith, Yusuke Yakushiji, Dilek Necioglu Orken, Franz Fazekas, Vincent Thijs, Ji Hoe Heo, Vincent Mok, Roland Veltkamp, Hakan Ay, Toshio Imaizumi, Beatriz Gomez-Anson, Kui Kai Lau, Eric Jouvent, Peter M. Rothwell, Kazunori Toyoda, Hee-Joon Bae, Joan Marti-Fabregas, David J. Werring, Kirsty Harkness, Louise Shaw, Jane Sword, Azlisham Mohd Nor, Pankaj Sharma, Deborah Kelly, Frances Harrington, Marc Randall, Matthew Smith, Karim Mahawish, Abduelbaset Elmarim, Bernard Esisi, Claire Cullen, Arumug Nallasivam, Christopher Price, Adrian Barry, Christine Roffe, John Coyle, Ahamad Hassan, Jonathan Birns, David Cohen, Lakshmanan Sekaran, Adrian Parry-Jones, Anthea Parry, David Hargroves, Harald Proschel, Prabel Datta, Khaled Darawil, Aravindakshan Manoj, Mathew Burn, Chris Patterson, Elio Giallombardo, Nigel Smyth, Syed Mansoor, Ijaz Anwar, Rachel Marsh, Sissi Ispoglou, Dinesh Chadha, Mathuri Prabhakaran, Sanjeevikumar Meenakishundaram, Janice O'Connell, Jon Scott, Vinodh Krishnamurthy, Prasanna Aghoram, Michael McCormick, Nikola Sprigg, Paul O'Mahony, Martin Cooper, Lillian Choy, Peter Wilkinson, Simon Leach, Sarah Caine, Ilse Burger, Gunaratam Gunathilagan, Paul Guyler, Hedley Emsley, Michelle Davis, Dulka Manawadu, Kath Pasco, Maam Mamun, Robert Luder, Mahmud Sajid, James Okwera, Elizabeth Warburton, Kari Saastamoinen, Timothy England, Janet Putterill, Enrico Flossman, Michael Power, Krishna Dani, David Mangion, Appu Suman, John Corrigan, Enas Lawrence, Djamil Vahidassr, Clare Shakeshaft, Martin Brown, Andreas Charidimou, Hannah Cohen, Gargi Banerjee, Henry Houlden, Mark White, Tarek Yousry, Enrico Flossmann, Keith Muir, Marwan el-Koussy, Pascal Gratz, Jeremy Molad, Amos Korczyn, Efrat Kliper, Philippe Maeder, Achim Gass, Chahin Pachai, Luc Bracoub, Marie-Yvonne Douste-Blazy, Marie Dominique Fratacci, Eric Vicaut, Shoichiro Sato, Kaori Miwa, Kyohei Fujita, Toshihiro Ide, Henry Ma, John Ly, Shahoo Singhal, Ronil Chandra, Lee-Anne Slater, Cathy Soufan, Christopher Moran, Christopher Traenka, Sebastian Thilemann, Joachim Fladt, Henrik Gensicke, Leo Bonati, Beom Joon Kim, Moon-Ku Han, Jihoon Kang, Eunbin Ko, Mi Hwa Yang, Myung Suk Jang, Sean Murphy, Fiona Carty, Layan Akijian, John Thornton, Mark Schembri, Elles Douven, Raquel Delgado-Mederos;, Rebeca Marín, Pol Camps-Renom, Daniel Guisado-Alonso, Fidel Nuñez, Santiago Medrano-Martorell, Elisa Merino, Kotaro Iida, Syuhei Ikeda, Masashi Nishihara, Hiroyuki Irie, Derya Selcuk Demirelli, Jayesh Modi Medanta, Charlotte Zerna, Maria Valdés Hernández, Paul Armitage, Anna Heye, Susana Muñoz-Maniega, Eleni Sakka, Michael Thrippleton, Martin Dennis, Ysoline Beigneux, Mauro Silva, Narayanaswamy Venketasubramanian, Shu Leung Ho, Raymond Tak Fai Cheung, Koon Ho Chan, Kay Cheong Teo, Edward Hui, Joseph Shiu Kwong Kwan, Richard Chang, Man Yu Tse, Chu Peng Hoi, Chung Yan Chan, Oi Ling Chan, Ryan Hoi Kit Cheung, Edmund Ka Ming Wong, Kam Tat Leung, Suk Fung Tsang, Hing Lung Ip, Sze Ho Ma, Karen Ma, Wing Chi Fong, Siu Hung Li, Richard Li, Ping Wing Ng, Kwok Kui Wong, Wenyan Liu, Lawrence Wong, Lino Ramos, Els de Schryver, Joost Jöbsis, Jaap van der Sande, Paul Brouwers, Yvo Roos, Jan Stam, Stef Bakker, Henk Verbiest, Wouter Schoonewille, Cisca Linn, Leopold Hertzberger, Maarten van Gemert, Paul Berntsen, Jeroen Hendrikse, Paul Nederkoorn, Werner Mess, Peter Koudstaal, Alexander Leff, Nicholas Ward, Parashkev Nachev, Richard Perry, Hatice Ozkan, John Mitchell

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    Abstract

    Background: Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. Methods: We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. Findings: Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years [IQR 0·19–2·44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1·35 (95% CI 1·20–1·50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2·45 (1·82–3·29) for intracranial haemorrhage and 1·23 (1·08–1·40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4·55 [95% CI 3·08–6·72] for intracranial haemorrhage vs 1·47 [1·19–1·80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5·52 [3·36–9·05] vs 1·43 [1·07–1·91]; and for ≥20 cerebral microbleeds, aHR 8·61 [4·69–15·81] vs 1·86 [1·23–1·82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48–84] per 1000 patient-years vs 27 intracranial haemorrhages [17–41] per 1000 patient-years; and for ≥20 cerebral microbleeds, 73 ischaemic strokes [46–108] per 1000 patient-years vs 39 intracranial haemorrhages [21–67] per 1000 patient-years). Interpretation: In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden. Funding: British Heart Foundation and UK Stroke Association.
    Original languageEnglish
    Pages (from-to)653-665
    JournalThe Lancet Neurology
    Volume18
    Issue number7
    DOIs
    Publication statusPublished - 1 Jul 2019

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