Can cerebral microbleeds predict stroke recurrence?
Authors: Georgios Tsivgoulis, Aristeidis H Katsanos
Journal: The Lancet Neurology (2019)

Should patients with a history of ischaemic stroke or transient ischaemic attack be treated with antithrombotic drugs? The answer to this question has been considered to be clear and straightforward for more than two decades.1Sandercock PA Counsell C Tseng MC Cecconi E Oral antiplatelet therapy for acute ischaemic stroke.Cochrane Database Syst Rev. 2014; 3 (CD000029.)Google Scholar, 2Hart RG Benavente O McBride R Pearce LA Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis.Ann Intern Med. 1999; 131: 492-501Crossref PubMed Scopus (1512) Google Scholar However, the question regarding the balance of future intracranial bleeding risk compared with risk of recurrent ischaemic stroke in patients with high burden of cerebral microbleeds remains one of the most complicated problems of modern stroke medicine.3Shoamanesh A Charidimou A Sharma M Hart RG Should patients with ischemic stroke or transient ischemic attack with atrial fibrillation and microbleeds be anticoagulated?.Stroke. 2017; 48: 3408-3412Crossref PubMed Scopus (16) Google Scholar In The Lancet Neurology, Duncan Wilson and colleagues4Wilson D Ambler G Lee K-J et al.Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.Lancet Neurol. 2019; (published online May 23.)http://dx.doi.org/10.1016/S1474-4422(19)30197-8Summary Full Text Full Text PDF Scopus (103) Google Scholar aim to elucidate the association between cerebral microbleed burden in baseline neuroimaging and the risk of recurrent stroke. The study was a pooled analysis of individual patient data from 20 322 patients (mean age 70 years [SD 13]) with history of ischaemic stroke or transient ischaemic attack from 38 cohort studies.4Wilson D Ambler G Lee K-J et al.Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.Lancet Neurol. 2019; (published online May 23.)http://dx.doi.org/10.1016/S1474-4422(19)30197-8Summary Full Text Full Text PDF Scopus (103) Google Scholar After a cumulative follow-up of 35 225 patient-years (median 1·34 years [IQR 0·19–2·44]) the investigators documented that cerebral microbleed presence in baseline neuroimaging was associated with increased risk for both ischaemic stroke and intracranial haemorrhage. Despite the fact that the adjusted hazard ratio (aHR) for intracranial haemorrhage was nearly five times higher than that for ischaemic stroke for patients with five or more or ten or more cerebral microbleeds and nearly eight times higher for patients with 20 or more cerebral microbleeds, the absolute rate of ischaemic stroke exceeded that of intracranial haemorrhage even in patients with high (≥20) cerebral microbleed burden.4Wilson D Ambler G Lee K-J et al.Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.Lancet Neurol. 2019; (published online May 23.)http://dx.doi.org/10.1016/S1474-4422(19)30197-8Summary Full Text Full Text PDF Scopus (103) Google Scholar Notably, all associations were independent from cerebral microbleed anatomical distribution (lobar vs mixed vs deep), antithrombotic treatment (antiplatelet or anticoagulant), ethnicity (white vs non-white), age (>80 years vs ≤80 years), and the presence of white-matter hyperintensities on baseline neuroimaging or the diagnosis of probable cerebral amyloid angiopathy.4Wilson D Ambler G Lee K-J et al.Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.Lancet Neurol. 2019; (published online May 23.)http://dx.doi.org/10.1016/S1474-4422(19)30197-8Summary Full Text Full Text PDF Scopus (103) Google Scholar The main strengths of this study are the large sample size, including almost all available findings from published and unpublished cohort studies of adults with recent ischaemic stroke or transient ischaemic attack using appropriate MRI sequence sensitive to magnetic susceptibility, the prospective study design with strict inclusion and exclusion criteria, and the comprehensive, prespecified, and robust statistical analysis plan. This study offers novel and clinically relevant information that in patients with recent ischaemic stroke or transient ischaemic attack the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, burden, or pattern and independently of their secondary prevention treatment with antiplatelets or oral anticoagulants. Notably, the individual-patient-data meta-analysis credibly contradicts the findings of a previous meta-analysis that did not detect any association between cerebral microbleed presence or burden and recurrent ischaemic stroke in patients with ischaemic stroke treated with oral anticoagulants.5Charidimou A Karayiannis C Song TJ et al.Brain microbleeds, anticoagulation, and hemorrhage risk: meta-analysis in stroke patients with AF.Neurology. 2017; 89: 2317-2326Crossref PubMed Scopus (71) Google Scholar However, the observational study design is prone to residual confounding, and selection and indication biases. Furthermore, the investigators were unable to adjust for other cofounders in their multivariable models, including MRI field strength, other secondary prevention therapies (eg, statins), and vascular risk factors such as diabetes mellitus and chronic kidney disease. Additionally, no central adjudication of the outcome events and no formal assessment of recurrent stroke severity and residual disability were done. The authors report the absence of any interaction between oral anticoagulant type (vitamin K antagonists [vs non-vitamin K oral anticoagulants]) and cerebral microbleed presence for the outcomes of recurrent ischaemic stroke and intracranial haemorrhage, but this finding might be attributed to the modest number of outcome events and particularly intracranial haemorrhages (n=91) as well as to potential imbalances between vitamin K antagonists (n=5253) and non-vitamin K oral anticoagulants (n=2484) subgroups. The protective effect of non-vitamin K oral anticoagulants (compared with vitamin K antagonists) in the risk of incident intracranial bleeding in patients with atrial fibrillation receiving anticoagulation for secondary stroke prevention has been well established.6Chatterjee S Sardar P Biondi-Zoccai G Kumbhani DJ New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation.JAMA Neurol. 2013; 70: 1486-1490PubMed Google Scholar In conclusion, the study by Wilson and colleagues4Wilson D Ambler G Lee K-J et al.Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.Lancet Neurol. 2019; (published online May 23.)http://dx.doi.org/10.1016/S1474-4422(19)30197-8Summary Full Text Full Text PDF Scopus (103) Google Scholar highlights that the absolute risk of recurrent ischaemic stroke consistently exceeds the absolute risk of intracranial haemorrhage in patients with a history of ischaemic stroke or transient ischaemic attack even in the presence of high cerebral microbleed load (≥20). These findings suggest that cerebral microbleed presence, burden, and pattern on neuroimaging should not influence the decision to select appropriate antithrombotic therapy for secondary stroke prevention. Additional research is required to establish whether cerebral microbleeds should be incorporated as a neuroimaging marker in clinical risk prediction scores of recurrent ischaemic stroke or intracranial haemorrhage in patients with recent cerebral ischaemia treated with oral anticoagulants or antiplatelet drugs. We declare no competing interests. Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studiesIn 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. Full-Text PDF Open Access