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

Microbleeds International Collaborative Network, 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 PurruckerBonnie Yin Ka Lam, Adrian 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 Kvan 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, Joanna M Wardlaw, Simon Jung, Eleni Sakka (Member of Group Organisation), Richard Perry (Member of Group Organisation), John Mitchell (Member of Group Organisation)

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 [1·23–2·82]). 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
Number of pages13
JournalLancet Neurology
Issue number7
Early online date23 May 2019
Publication statusPublished - 1 Jul 2019


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