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.
Bibliographical noteFunding Information:
Funding for the included cohort studies was provided by the British Heart Foundation, Stroke Association, UCLH 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 AG, 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.
MK reports grants from the Ministry of Health, Labour and Welfare, Japan, and from the National Cerebral and Cardiovascular Center during the conduct of the study; and speaker honoraria from Bayer Yakuhin, Daiichi-Sankyo Company, and Bristol-Myers Squibb (BMS)/Pfizer. HC reports participation in the steering committee for a clinical trial supported by Servier and was a consultant for Hovid Inc. EMA reports personal fees from Pfizer, Boehringer Ingelheim, Nutricia, Abbott, and Sanofi, outside the submitted work. JP reports personal fees from Boehringer Ingelheim and Akcea and personal fees and non-financial support from Pfizer outside the submitted work. EBA reports grants from US–Israel Bi-national Science Foundation, The American Federation for Aging Research, and The Israeli Chief Scientist, Ministry of Health, during the conduct of the study. SBC reports grants from the Canadian Institute of Health Research and a Pfizer Cardiovascular award during the conduct of the study. DJS reports other funding from Bayer and from BMS/Pfizer outside the submitted work. PL reports other funding from Daiichi-Sankyo, Bayer, and Boehringer Ingelheim, outside the submitted work. RA-SS reports grants from the British Heart Foundation, The Stroke Association, and Chest Heart & Stroke Scotland outside the submitted work. GYHL reports consultancy for Bayer/Janssen, BMS/Pfizer, Biotronik, Medtronic, Boehringer Ingelheim, Microlife, and Daiichi-Sankyo; and speaker honoraria from Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, Microlife, Roche, and Daiichi-Sankyo. HPM reports personal fees from Neuravi/Cerenovus, Medtronic, Bayer, Daiichi-Sankyo, and Servier outside the submitted work. DH reports grants from University College Dublin Newman Fellowship supported Bayer during the conduct of the study. MEK reports grants from the Center for Translational Molecular Medicine during the conduct of the study. AMT reports grants from the Dutch Heart Foundation during the conduct of the study. AvdL reports grants from the Center for Translation Molecular Medicine and Dutch Heart Foundation during the conduct of the study. JMW reports grants from Wellcome Trust, Chest Heart Stroke Scotland, and Row Fogo Charitable Trust during the conduct of the study. YS reports a grant from Health and Medical Research Fund. VIHK reports grants from the Netherlands Heart Foundation (grant 2001B071) during the conduct of the study. STE reports grants from Daiichi-Sankyo, Bayer, Pfizer, and Swiss Heart Foundation during the conduct of the study; other funding from Daiichi-Sankyo, Mindmaze, and Stago; and grants from the Swiss National Science Foundation outside the submitted work. NP reports other funding from Daiichi-Sankyo, Bayer, and Boehringer Ingelheim outside the submitted work. EES reports personal fees from Portola Pharmaceuticals and Alnylam Pharmaceuticals outside the submitted work. VT reports personal fees and non-financial support from Boehringer Ingelheim and personal fees from Bayer, Pfizer/BMS, and Amgen and Medtronic outside the submitted work. RV reports grants and personal fees from Bayer, Boehringer Ingelheim, BMS, Daiichi-Sankyo, and Medtronic; and personal fees from Morphosys and Amgen outside the submitted work. HA reports grants from National Institutes of Health during the conduct of the study. PMR reports personal fees from Bayer outside the submitted work. KT reports personal fees from Daiichi-Sankyo, Bayer Yakuhin, BMS, and Nippon Boehringer Ingelheim outside the submitted work. DJWe reports personal fees from Bayer outside the submitted work. All other authors declare no competing interests.
All Science Journal Classification (ASJC) codes
- Clinical Neurology