| dc.description.sponsorship | Our large-scale pooled analysis of individual patient data confirms that, in patients with recent ischaemic stroke or transient ischaemic attack treated with antithrombotic drugs, cerebral microbleeds are associated with the subsequent risks of symptomatic intracranial haemorrhage and ischaemic stroke; as cerebral microbleed burden increases, the relative risk (aHR) of intracranial haemorrhage rises more steeply than that of ischaemic stroke. Our most important new finding is that, regardless of cerebral microbleed burden and distribution (ie, mixed, deep, or lobar), or the type of antithrombotic treatment received (oral anticoagulants or antiplatelet therapy), the absolute risk of ischaemic stroke is consistently substantially higher than that of intracranial haemorrhage. As well as confirming the association between cerebral microbleeds and both recurrent ischaemic stroke and symptomatic intracranial haemorrhage found in smaller cohorts of patients with ischaemic stroke and transient ischaemic attack treated with antiplatelet drugs 28 or oral anticoagulants, 27,57,35 the large number of participants has improved the precision of our estimates of stroke recurrence rates and relative hazards, while the inclusion of individual patient data allowed adjustment for potential confounding factors. Our study also adds new data for the important subgroups of patients with many (eg, ?20) cerebral microbleeds, which cause the most clinical concern and could not be addressed by any of the previously published meta-analyses. The association of cerebral microbleeds with a consistently higher rate of ischaemic stroke than intracranial haemorrhage suggests that cerebral microbleeds are a marker for cerebral small vessel diseases that can cause not only intracranial haemorrhage, but also ischaemic stroke. Although it has been inferred that cerebral microbleeds are a marker of direct extravasation of red blood cells from arterioles and capillaries damaged by bleeding-prone arteriopathies, alternative non-haemorrhagic mechanisms include ischaemia-mediated iron store release by oligodendrocytes 10 or phagocytosis of red cell microemboli into the perivascular space. 11 A report of haemorrhagic transformation of small acute microinfarcts into cerebral microbleeds provides direct evidence that cerebral microbleeds can result from ischaemic mechanisms. 13 These varied mechanisms underlying cerebral microbleeds might explain why even patients at the highest risk of intracranial haemorrhage still have a higher absolute risk of ischaemic stroke. Moreover, patients with cerebral microbleeds often have multiple vascular risk factors, so are at risk of not only small vessel ischaemic stroke but also other ischaemic stroke subtypes. 58 Patients with cerebral microbleeds usually also have white matter hyperintensities, which are associated with the risk of recurrent stroke, death, and poor functional outcome after ischaemic stroke 59 and might also contribute to the increased risk of ischaemic stroke associated with cerebral microbleeds. We found no evidence that a strictly lobar pattern of cerebral microbleeds (fulfilling the Boston criteria for probable CAA, 5 causing clinical concern for intracranial bleeding risk 35 ) is associated with the risk of intracranial haemorrhage or ischaemic stroke. These findings might reflect low diagnostic accuracy when using cerebral microbleeds for diagnosis of CAA in patients without intracerebral haemorrhage or dementia, 60 rather than a true absence of any association of CAA with intracranial haemorrhage. Furthermore, the aHRs for intracranial haemorrhage associated with lobar cerebral microbleeds (compared with patients without lobar cerebral microbleeds [including none]) were closer to those associated with deep or mixed cerebral microbleeds (compared with patients without deep or mixed cerebral microbleeds [including none]). Our results differ from some previous observations in smaller cohorts. First, in contrast to a smaller two-centre study, 29 we did not find that the risk of intracranial haemorrhage approached the risk of ischaemic stroke after 1 year. Rather, we found that the rate of ischaemic stroke was consistently higher than that of intracranial haemorrhage, and the aHRs associated with cerebral microbleeds for both ischaemic stroke and intracranial haemorrhage remained stable over time. Second, our data indicate a smaller increase in the relative risk of intracranial haemorrhage for patients with five or more cerebral microbleeds than reported in a previous smaller meta-analysis, 28 but our much larger individual participant sample size allowed us to investigate high cerebral microbleed burdens (five or more, ten or more, and 20 or more) with adjustment for confounders and greater statistical precision and power. The comparatively low frequency of symptomatic intracranial haemorrhage after ischaemic stroke or transient ischaemic attack and the consistently higher risk of recurrent ischaemic stroke make randomised controlled trials of antithrombotic treatment (themselves proven in large randomised trials) guided by cerebral microbleeds challenging. However, ongoing and future randomised controlled trials should provide further insights. The MRI substudy in the RESTART trial 61 of antiplatelet therapy after intracerebral haemorrhage excluded all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds, but also illustrates how very large sample sizes are probably required to identify statistically significant interactions in smaller cerebral microbleed subgroups in current (eg, the MRI substudy of NAVIGATE ESUS [ NCT02313909 ]) and future randomised controlled trials. Nevertheless, our large collaborative pooled analysis provides the best available evidence on the associations of cerebral microbleeds with subsequent intracranial haemorrhage and ischaemic stroke after ischaemic stroke or transient ischaemic attack. We included data from a worldwide collaborative network, making our results globally generalisable. The large individual patient dataset provides high statistical power and precision for risk estimates, allowing us to explore associations with several clinically important primary outcomes, while adjusting for important prognostic variables to minimise confounding. Included cohorts used validated rating instruments for cerebral microbleeds, and we adjusted for the use of different MRI sequences (T2* GRE or SWI) to detect cerebral microbleeds, which accounts for the higher sensitivity of SWI for detecting cerebral microbleeds compared with T2* GRE. 62 We followed a published statistical analysis plan and confirmed our findings in a two-stage meta-analysis, indicating the robustness of our results. In terms of limitations, our observational design has potential for selection bias and confounding of antithrombotic therapy by indication or unmeasured physician factors; thus, the relative hazards (aHRs) for intracranial haemorrhage and ischaemic stroke must be interpreted with caution. To definitively establish whether cerebral microbleeds modify the net clinical benefit of antithrombotic drugs would require a randomised controlled trial. Many of the included studies did not formally adjudicate events. The requirement for MRI-suitable patients probably led to the inclusion of less severe strokes than an unselected population. Even with the many individual patients included, we could not precisely estimate risks associated with an extremely large number of cerebral microbleeds (eg, ?50), but such patients are very rare in clinical practice. Although we adjusted for known prognostic variables, residual confounding secondary to unknown or uncontrolled factors such as stroke mechanism could still have affected our results. Furthermore, we were unable to include some candidate variables in our multivariable models because they were not sufficiently widely available across all participating cohorts (eg, white matter hyperintensities, MRI field strength, diabetes, ischaemic heart disease, renal function, and statin use on discharge). Our analyses did not formally assess net clinical benefit, accounting for the greater severity of intracranial haemorrhage compared with recurrent ischaemic stroke. In summary, our large-scale pooled analysis in patients with recent ischaemic stroke or transient ischaemic attack found that the absolute risk of ischaemic stroke is consistently higher than that of intracranial haemorrhage, regardless of the number or anatomical distribution of cerebral microbleeds. However, cerebral microbleeds are associated with a greater relative hazard (aHR) for intracranial haemorrhage than ischaemic stroke; further studies are needed to establish the usefulness of neuroimaging biomarkers, including cerebral microbleeds, in improving risk prediction scores for intracranial haemorrhage and ischaemic stroke. Contributors DJWe, DW, GA, and JM-F drafted the initial protocol, which was reviewed with critical revisions and approval by all authors. DW and GA did the statistical analysis. DW, DJW, and GA wrote the first draft of the manuscript. All authors contributed to data acquisition, management, and brain imaging analyses. All authors contributed to critical revision of the manuscript and approved the final manuscript for submission. Declaration of interests 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. Acknowledgments 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. | en_US |
