Development of imaging-based risk scores for prediction of intracranial haemorrhage and ischaemic stroke in patients taking antithrombotic therapy after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies - 18/03/21
Doi : 10.1016/S1474-4422(21)00024-7
Jonathan G Best, MD a, Gareth Ambler, PhD b, Duncan Wilson, PhD a, c, Keon-Joo Lee, MD d, Jae-Sung Lim, MD e, Masayuki Shiozawa, MD f, Masatoshi Koga, MD f, Linxin Li, DPhil g, Caroline Lovelock, FRACP g, Hugues Chabriat, ProfMD h, i, j, Michael Hennerici, ProfMD k, Yuen Kwun Wong, MSc l, Henry Ka Fung Mak, MD m, Luis Prats-Sanchez, PhD n, Alejandro Martínez-Domeño, MD n, Shigeru Inamura, MD p, Kazuhisa Yoshifuji, PhD p, Ethem Murat Arsava, MD q, Solveig Horstmann, MD r, Jan Purrucker, MD r, Bonnie Yin Ka Lam, PhD s, Adrian Wong, PhD s, Young Dae Kim, MD t, Tae-Jin Song, MD u, Robin Lemmens, PhD v, w, Sebastian Eppinger, MD x, Thomas Gattringer, MD x, Ender Uysal, MD y, Zeynep Tanriverdi, MD z, Natan M Bornstein, MD aa, ab, Einor Ben Assayag, PhD aa, ab, Hen Hallevi, MD aa, ab, Jeremy Molad, MD aa, ab, Masashi Nishihara, MD ac, Jun Tanaka, MD ad, Shelagh B Coutts, ProfMD ae, Alexandros Polymeris, MD af, Benjamin Wagner, MD af, David J Seiffge, MD a, af, ao, Philippe Lyrer, ProfMD af, Ale Algra, ProfMD ag, ah, L Jaap Kappelle, ProfMD ah, Rustam Al-Shahi Salman, ProfPhD aj, Hans R Jäger, ProfFRCR ak, Gregory Y H Lip, ProfMD al, am, an, Urs Fischer, ProfMD ao, Marwan El-Koussy, ProfMD ap, Jean-Louis Mas, ProfMD aq, Laurence Legrand, MD ar, Christopher Karayiannis, MD as, Thanh Phan, ProfMD at, Sarah Gunkel, MD au, Nicolas Christ, MD au, Jill Abrigo, MD av, Thomas Leung, ProfMD aw, Winnie Chu, ProfMD av, Francesca Chappell, PhD ax, ay, Stephen Makin, PhD az, Derek Hayden, MD ba, bb, David J Williams, ProfPhD bc, bd, Werner H Mess, ProfMD be, Paul J Nederkoorn, MD bf, Carmen Barbato, MD a, bg, Simone Browning, BSc a, bg, Kim Wiegertjes, MD bh, Anil M Tuladhar, MD bh, Noortje Maaijwee, PhD bi, Anne Cristine Guevarra, MD bj, Chathuri Yatawara, PhD bj, Anne-Marie Mendyk, RN bk, Christine Delmaire, MD bk, bl, Sebastian Köhler, PhD bm, Robert van Oostenbrugge, ProfMD bn, Ying Zhou, PhD bo, Chao Xu, MD bo, Saima Hilal, PhD bp, Bibek Gyanwali, MD bp, Christopher Chen, FRCP bp, Min Lou, ProfPhD bo, Julie Staals, MD bn, Régis Bordet, ProfMD bk, Nagaendran Kandiah, FRCP bj, Frank-Erik de Leeuw, ProfMD bh, Robert Simister, PhD a, bg, Jeroen Hendrikse, ProfMD ai, Peter J Kelly, ProfMD ba, Joanna Wardlaw, ProfMD ax, ay, Yannie Soo, MD aw, Felix Fluri, MD au, Velandai Srikanth, ProfPhD as, David Calvet, ProfMD aq, Simon Jung, ProfMD ao, Vincent I H Kwa, MD bq, Stefan T Engelter, ProfMD af, br, Nils Peters, ProfMD af, br, Eric E Smith, ProfMD ae, Hideo Hara, ProfPhD ad, Yusuke Yakushiji, ProfPhD ad, bs, Dilek Necioglu Orken, ProfMD bt, Franz Fazekas x, Vincent Thijs, ProfMD bu, bv, Ji Hoe Heo, ProfMD t, Vincent Mok, ProfMD s, Roland Veltkamp, ProfMD r, bw, Hakan Ay, MD q, bx, Toshio Imaizumi, MD p, Beatriz Gomez-Anson, FRCR o, Kui Kai Lau, DPhil l, Eric Jouvent, ProfMD h, i, j, Peter M Rothwell, ProfFMedSci g, Kazunori Toyoda, ProfMD f, Hee-Joon Bae, ProfPhD d, Joan Marti-Fabregas, ProfPhD n, David J Werring, ProfPhD a, ⁎ 
on behalf of the
on behalf of the
Microbleeds International Collaborative Network
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, Ijaz Anwar, 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, Kirsty Harkness, Enrico Flossmann, Nigel Smyth, Louise Shaw, Elizabeth Warburton, Keith Muir, Pascal Gratz, Heinrich Mattle, Leonidas Panos, 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, Shaloo 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, 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, Dianne Van Dam-Nolen, M Eline Kooi, Aad Van der Lugt, Peter Koudstaal, Alexander Leff, Nicholas Ward, Parashkev Nachev, Richard Perry, Hatice Ozkan, John Mitchell
a UCL Stroke Research Centre, Department of Brain Repair and Rehabilitation, University College London Queen Square Institute of Neurology, London, UK
b Department of Statistical Science, University College London, Gower Street, London, UK
c New Zealand Brain Research Institute, Christchurch, New Zealand
d Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
e Department of Neurology, Hallym Neurological Institute, Hallym University College of Medicine, Hallym University Sacred Heart Hospital, Anyang, South Korea
f Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Centre, Suita, Japan
g Wolfson Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
h Assistance Publique - Hôpitaux de Paris, Lariboisière Hospital, Department of Neurology, Paris, France
i Federation Hospitalo-Universitaire NeuroVasc, Université de Paris, Paris, France
j INSERM U1141, Paris, France
k Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany
l Division of Neurology, Department of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
m Department of Diagnostic Radiology, The University of Hong Kong, Hong Kong Special Administrative Region, China
n Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute, Barcelona, Spain
o Unit of Neuroradiology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute, Barcelona, Spain
p Department of Neurosurgery, Kushiro City General Hospital, Kushiro, Japan
q A A Martinos Center for Biomedial Imaging, Department of Neurology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA
r Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany
s Therese Pei Fong Chow Research Centre for Prevention of Dementia, Gerald Choa Neuroscience Centre, Lui Che Woo Institute of Innovative Medicine, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
t Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
u Department of Neurology, Seoul Hospital, Ewha Womans University College of Medicine, Seoul, South Korea
v Experimental Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, Leuven, Belgium
w Vlaams Instituut voor Biotechnologie, Center for Brain & Disease Research; Department of Neurology, University Hospitals Leuven, Leuven, Belgium
x Department of Neurology, Medical University of Graz, Graz, Austria
y Department of Radiology, Saglık Bilimleri University, Sisli Etfal Education and Research Hospital, Istanbul, Turkey
z Department of Neurology, İzmir Katip Çelebi University Atatürk Education and Research Hospital, İzmir Turkey
aa Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
ab Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
ac Department of Radiology, Saga University Faculty of Medicine, Saga, Japan
ad Division of Neurology, Department of Internal Medicine, Saga University Faculty of Medicine, Saga, Japan
ae Calgary Stroke Program, Department of Clinical Neurosciences, Radiology and Community Health Sciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
af Department of Neurology and Stroke Centre, University Hospital Basel and University of Basel, Switzerland
ag Julius Centre for Health Sciences and Primary Care, Utrecht University, Utrecht, The Netherlands
ah Department of Neurology and Neurosurgery, Utrecht University, Utrecht, The Netherlands
ai Department of Radiology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
aj Centre for Clinical Brain Sciences, School of Clinical Sciences, University of Edinburgh, Edinburgh, UK
ak Lysholm Department of Neuroradiology and the Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, University College London Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, UK
al Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool, UK
am Liverpool Heart & Chest Hospital, Liverpool, UK
an Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
ao Department of Neurology, University Hospital Inselspital Bern, University of Bern, Bern, Switzerland
ap Department of Diagnostic and Interventional Neuroradiology, University Hospital Inselspital Bern, University of Bern, Bern, Switzerland
aq Department of Neurology, Sainte-Anne Hospital, Institut de Psychiatrie et Neurosciences de Paris, INSERM, Université de Paris, Paris, France
ar Department of Neuroradiology, Sainte-Anne Hospital, Institut de Psychiatrie et Neurosciences de Paris, INSERM, Université de Paris, Paris, France
as Peninsula Clinical School, Peninsula Health, Monash University, Melbourne, Australia
at Stroke and Ageing Research Group, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Australia
au Department of Neurology, University Hospital of Würzburg, Würzburg, Germany
av Department of Imaging and Interventional Radiology, Prince of Wales Hospital, The Chinese University of Hong Kong, Special Administrative Region, China
aw Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Special Administrative Region, China
ax Centre for Clinical Brain Sciences, Edinburgh Imaging, University of Edinburgh, Edinburgh, UK
ay UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
az Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK
ba The Neurovascular Research Unit and Health Research Board, Stroke Clinical Trials Network Ireland, University College Dublin, Dublin, Ireland
bb Department of Medical Gerontology, Trinity College Dublin, Dublin, Ireland
bc Department of Geriatric and Stroke Medicine, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences Dublin, Ireland
bd Department of Geriatric and Stroke Medicine, Beaumont Hospital Dublin, Ireland
be Department of Clinical Neurophysiology, Maastricht University Medical Centre, Maastricht, the Netherlands
bf Department of Neurology, Amsterdam University Medical Centres, Netherlands
bg Comprehensive Stroke Service, University College London Hospitals NHS Trust, London, UK
bh Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Donders Centre for Medical Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands
bi Department for Neurology and Neurorehabilitation, Neurocenter, Lucerne State Hospital, Lucerne, Switzerland
bj Department of Neurology, National Neuroscience Institute, Singapore
bk Degenerative and vascular cognitive disorders, University of Lille, INSERM, Centre Hospitalier Universitaire de Lille, Lille, France
bl Department of Radiology, Fondation A de Rothschild, Paris, France
bm Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, The Netherlands
bn Department of Neurology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, The Netherlands
bo Department of Neurology, The 2nd affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China
bp Memory Aging & Cognition Centre, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
bq Department of Neurology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
br Neurology and Neurorehabilitation, Department of Geriatric Medicine FELIX PLATTER, University of Basel, Switzerland
bs Department of Neurology, Kansai Medical University, Osaka, Japan
bt Memorial Sisli Hospital, Department of Neurology, Istanbul, Turkey
bu Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, VIC, Australia
bv Department of Neurology, Austin Health, Heidelberg, VIC, Australia
bw Department of Brain Sciences, Imperial College London, London, UK
bx Takeda, Cambridge, MA, USA
*Correspondence to: Prof David J Werring, UCL Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, London WC1B 5EH, UKUCL Stroke Research CentreDepartment of Brain Repair and RehabilitationUCL Queen Square Institute of NeurologyLondonWC1B 5EHUK
Summary |
Background |
Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk.
Methods |
We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602.
Findings |
The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69–0·77) with a calibration slope of 0·94 (0·81–1·06) for the intracranial haemorrhage model and 0·63 (0·62–0·65) with a calibration slope of 0·97 (0·87–1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models.
Interpretation |
The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted.
Funding |
British Heart Foundation and Stroke Association.
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Vol 20 - N° 4
P. 294-303 - avril 2021 Retour au numéro
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