Article open access publication

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

The Lancet Neurology, Elsevier, ISSN 1474-4465

Volume 18, 7, 2019

DOI:10.1016/s1474-4422(19)30197-8, Dimensions: pub.1115219516, PMC: PMC6562236, PMID: 31130428,


Wilson, Duncan (1) (2) (3)
Bornstein, Natan M (23) (24)
Assayag, Einor Ben (23) (24)
Hallevi, Hen (23) (24)
Hert, Lisa (27)
Seiffge, David J (2) (3) (27) (28)
Algra, Ale (29) (30)
Lip, Gregory Y H (33) (34)
Williams, David J (42) (43)
Barbato, Carmen (2) (3) (46)
Browning, Simone (2) (3) (46)
Zhou, Ying (52)
Xu, Chao (52)
Lou, Min (52)
Simister, Robert (2) (3) (46)
Thijs, Vincent (55) (56) (57)
Veltkamp, Roland (15) (58)
Ay, Hakan (14)
Jouvent, Eric (8) (9)

* Corresponding author



  1. (1) New Zealand Brain Research Institute, Christchurch, New Zealand
  2. (2) University College London, grid.83440.3b
  3. (3) National Hospital for Neurology and Neurosurgery, London UK
  4. (4) Seoul National University Bundang Hospital, grid.412480.b
  5. (5) Hallym University Sacred Heart Hospital, grid.488421.3
  6. (6) National Cerebral and Cardiovascular Center, grid.410796.d
  7. (7) University of Oxford, grid.4991.5
  8. (8) Lariboisière Hospital, grid.411296.9
  9. (9) Paris Diderot University, grid.7452.4
  10. (10) Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany
  11. (11) University of Hong Kong, grid.194645.b
  12. (12) Hospital de Sant Pau, grid.413396.a
  13. (13) Kushiro City General Hospital, grid.415580.d
  14. (14) Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA
  15. (15) University Hospital Heidelberg, grid.5253.1
  16. (16) Chinese University of Hong Kong, grid.10784.3a
  17. (17) Yonsei University, grid.15444.30
  18. (18) Department of Neurology, Ewha Womans University College of Medicine, Seoul, South Korea
  19. (19) Flanders Institute for Biotechnology, grid.11486.3a
  20. (20) KU Leuven, grid.5596.f
  21. (21) Medical University of Graz, grid.11598.34
  22. (22) Department of Neurology, Demiroglu Bilim University, Istanbul, Turkey
  23. (23) Tel Aviv Sourasky Medical Center, grid.413449.f
  24. (24) Tel Aviv University, grid.12136.37
  25. (25) Saga University, grid.412339.e
  26. (26) University of Calgary, grid.22072.35
  27. (27) University of Basel, grid.6612.3
  28. (28) Department of Diagnostic and Interventional Neuroradiology and Department of Neurology Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland
  29. (29) University Medical Center Utrecht, grid.7692.a
  30. (30) Utrecht University, grid.5477.1
  31. (31) University of Edinburgh, grid.4305.2
  32. (32) National Hospital for Neurology and Neurosurgery, grid.436283.8
  33. (33) Aalborg University, grid.5117.2, AAU
  34. (34) Liverpool Heart and Chest Hospital, grid.415992.2
  35. (35) Paris Descartes University, grid.10992.33
  36. (36) Monash University, grid.1002.3
  37. (37) University Hospital Würzburg, grid.411760.5
  38. (38) Department of Imaging and Interventional Radiology, Prince of Wales Hospital, The Chinese University of Hong Kong, Ma Liu Shui, Hong Kong
  39. (39) Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Ma Liu Shui, Hong Kong
  40. (40) University of Glasgow, grid.8756.c
  41. (41) University College Dublin, grid.7886.1
  42. (42) Beaumont Hospital, grid.414315.6
  43. (43) Royal College of Surgeons in Ireland, grid.4912.e
  44. (44) Maastricht University Medical Centre, grid.412966.e
  45. (45) Erasmus University Medical Center, grid.5645.2
  46. (46) University College London Hospitals NHS Foundation Trust, grid.52996.31
  47. (47) Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Donders Centre for Medical Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands
  48. (48) Lucerne State Hospital; Switzerland Center for Neurology and Neurorehabilitation, Luzern, Switzerland
  49. (49) National Neuroscience Institute, grid.276809.2
  50. (50) Centre Hospitalier Regional et Universitaire de Lille, grid.410463.4
  51. (51) Maastricht University, grid.5012.6
  52. (52) Second Affiliated Hospital of Zhejiang University, grid.412465.0
  53. (53) National University Health System, grid.410759.e
  54. (54) Onze Lieve Vrouwe Gasthuis, grid.440209.b
  55. (55) Austin Health, grid.410678.c
  56. (56) Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia
  57. (57) Universitair Ziekenhuis Leuven, grid.410569.f
  58. (58) Imperial College London, grid.7445.2


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.


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