TY - JOUR
T1 - 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
T2 - a pooled analysis of individual patient data from cohort studies
AU - Microbleeds International Collaborative Network
AU - Best, Jonathan G.
AU - Ambler, Gareth
AU - Wilson, Duncan
AU - Lee, Keon Joo
AU - Lim, Jae Sung
AU - Shiozawa, Masayuki
AU - Koga, Masatoshi
AU - Li, Linxin
AU - Lovelock, Caroline
AU - Chabriat, Hugues
AU - Hennerici, Michael
AU - Wong, Yuen Kwun
AU - Mak, Henry Ka Fung
AU - Prats-Sanchez, Luis
AU - Martínez-Domeño, Alejandro
AU - Inamura, Shigeru
AU - Yoshifuji, Kazuhisa
AU - Arsava, Ethem Murat
AU - Horstmann, Solveig
AU - Purrucker, Jan
AU - Lam, Bonnie Yin Ka
AU - Wong, Adrian
AU - Kim, Young Dae
AU - Song, Tae Jin
AU - Lemmens, Robin
AU - Eppinger, Sebastian
AU - Gattringer, Thomas
AU - Uysal, Ender
AU - Tanriverdi, Zeynep
AU - Bornstein, Natan M.
AU - Ben Assayag, Einor
AU - Hallevi, Hen
AU - Molad, Jeremy
AU - Nishihara, Masashi
AU - Tanaka, Jun
AU - Coutts, Shelagh B.
AU - Polymeris, Alexandros
AU - Wagner, Benjamin
AU - Seiffge, David J.
AU - Lyrer, Philippe
AU - Algra, Ale
AU - Kappelle, L. Jaap
AU - Al-Shahi Salman, Rustam
AU - Jäger, Hans R.
AU - Lip, Gregory Y.H.
AU - Fischer, Urs
AU - Hui, Edward
AU - Chan, Chung Yan
AU - Li, Richard
AU - Wong, Kwok Kui
AU - Werring, David J
N1 - Funding Information:
MK reports grants from Ministry of Health, Labour and Welfare, Japan, and National Cerebral and Cardiovascular Center; and personal fees from Nippon Boehringer Ingelheim, Bayer Yakuhin, Daiichi-Sankyo, and Bristol-Myers Squibb and Pfizer, outside the submitted work. HC reports personal fees from Hovid, outside the submitted work. EMA reports personal fees from Daiichi Sankyo, Pfizer, Bayer Healthcare, Nutricia, Abbott, Fresenius Kabi, and Sanofi; and grants from Türkiye Bilimsel ve Teknolojik Araştırma Kurumu, outside the submitted work. JP reports personal fees from Abbott, Akcea, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer, outside the submitted work. NB reports personal fees from Pfizer Israel, Ever Neuro Pharma, Shire Israel, and Boehringer Ingelheim Israel, outside the submitted work. DJS is a scientific advisory board member for and report compensation used for research from Bayer and Pfizer, outside the submitted work. PL reports travel and advisory board compensation from Bayer; advisory board compensation from Daiichi Sankyo, Böhringer Ingelheim, and Amgen SA; and grants from Böhringer Ingelheim, Acticor, and Sanofi Aventis, outside the submitted work. GYHL reports consultancy and speaker fees from Bayer, Bayer and Janssen, Bristol-Myers Squibb and Pfizer, Medtronic, Boehringer Ingelheim, Microlife, Roche, and Daiichi-Sankyo, outside the submitted work; GYHL reports that no fees received personally. UF reports grants from Medtronic, consultancy fees paid to their institution from Medtronic, Stryker, and CSL Behring; and grants from Swiss National Science and Swiss Heart Foundation, outside the submitted work. DH reports grants from Bayer-University College Dublin Newman Fellowship, during the study. JS reports grants from Adriana van Rinsum Ponsen Stichting, during the study. NK reports personal fees from Eisai Pharmaceuticals; grants and personal fees from Novartis Pharmaceuticals and Schwabe Pharmaceuticals; and grants from Temasek Foundation, outside the submitted work. PJK reports grants from Health Research Board Ireland, during the study. JMW reports grants from Wellcome Trust, Chest Heart Stroke Scotland, and Row Fogo Charitable Trust, during the study; grants from Fondation Leducq, British Heart Foundation, UK Dementia Research Institute funded by Medical Research Council, Alzheimer's Society and Alzheimer's Research UK, and Stroke Association, outside the submitted work. VIHK reports grants from Netherlands Heart Foundation (grant 2001B071) during the study. STE reports grants from Daiichi-Sankyo; dvisory board compensation from Bayer; and travel support for conferences from Bristol-Meyers Squibb, outside the submitted work. NP reports grants from Swiss Heart Foundation, during the study; advisory board compensation from Daiichi-Sankyo and Bayer; advisory board compensation and travel expenses from Boehringer Ingelheim; and grants from Swiss National Science Foundation, outside the submitted work. EES reports personal fees from Alnylam Pharmaceuticals, Bayer, and Portola, outside the submitted work. VT reports personal fees from Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Bayer, and Medtronic, outside the submitted work. RV reports grants and personal fees from Bayer and Bristol-Myers Squibb; grants from Boehringer, Daiichi-Sankyo, Medtronic, and Biogen; and personal fees from Javelin, outside the submitted work. KKL reports grants, personal fees and non-financial support from Boehringer Ingelheim; grants and non-financial support from Pfizer; grants and personal fees from Amgen; grants from Eisai; grants and personal fees from Sanofi; and non-financial support from Daiichi Sankyo; outside the submitted work. PMR reports personal fees from Bayer, Abbott, and Bristol-Myers Squibb, outside the submitted work. KT reports personal fees from Daiichi-Sankyo, Bayer Yakuhin, Bristol-Myers Squibb, and Nippon Boehringer Ingelheim, outside the submitted work. BHJ reports grants from Bristol-Myers Squibb Korea, Shinpoong Pharm, Bayer, Boehringer Ingelheim, and Daiichi-Sankyo; grants and personal fees from Esai; grants from AstraZeneca Korea, Servier Korea, Yuhan Corporation, Jeil Pharmaceutical, and Korean Drug; grants and personal fees from Shire Korea, grants from JLK inspection, Chong Gun Dang Pharmaceutical, and Dong-A Pharmaceutical; and personal fees from Amgen Korea and Otsuka Korea, outside the submitted work. JMF reports grants from Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias, and Instituto de Salud Carlos III, RETICS INVICTUS PLUS RD16/0010/0019, during the study. DJWe reports personal fees from Bayer, Alnylam, and Portola, outside the submitted work. All other authors declare no competing interests.
Funding Information:
Funding for the included cohort studies was provided by the British Heart Foundation, Stroke Association, University College London Hospitals National Institute of Health Research (NIHR) Biomedical Research Centre, Wellcome Trust, Health Research Board Ireland, NIHR Biomedical Research Centre (Oxford, UK), Canadian Institutes of Health Research, Pfizer Cardiovascular Research award, Basel Stroke Funds, Science Funds Rehabilitation Felix-Platter-Hospital, Neurology Research Pool University Hospital Basel, Bayer, Fondo de Investigaciones Sanitarias Instituto de Salud Carlos III (FI12/00296; RETICS INVICTUS PLUS RD16/0019/0010; FEDER), Imperial College London NIHR Biomedical Research Centre, Dutch Heart Foundation, Servier, Association de Recherche en Neurologie Vasculaire and RHU TRT_cSVD (ANR-16-RHUS-004), Vidi innovational grant from The Netherlands ZonMw, Chest Heart Stroke Scotland, Medical Research Council, Fondation Leducq, The Row Fogo Charitable Trust, National Institute of Health (USA), Adriana van Rinsum-Ponsen Stichting, Japan Agency for Medical Research and Development (AMED), Ministry of Health, Labour and Welfare (Japan), and National Cerebral and Cardiovascular Center, Health and Medical Research Grant, Singapore National Medical Research Council, and Dutch Heart Foundation. RS is part funded by the University College London Hospitals/University College London Biomedical Research Centre. RV is an investigator of Imperial Biomedical Research Centre and partly funded by the European Union's Horizon 2020 research and innovation programme under grant agreement No. 754517 (PRESTIGE-AF).
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85102586910&partnerID=8YFLogxK
U2 - 10.1016/S1474-4422(21)00024-7
DO - 10.1016/S1474-4422(21)00024-7
M3 - Journal article
C2 - 33743239
AN - SCOPUS:85102586910
SN - 1474-4422
VL - 20
SP - 294
EP - 303
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 4
ER -