Risk of intracerebral haemorrhage in Chinese patients with atrial fibrillation on warfarin with cerebral microbleeds: the IPAAC-Warfarin study

Soo, Yannie; Abrigo, Jill; Leung, Kam Tat; Tsang, Suk Fung; Ip, Hing Lung; Ho, Sze; Ma, Karen; Fong, Wing Chi; Li, Siu Hung; Li, Richard; Ng, Ping Wing; Wong, Kwok Kui; Liu, Wenyan; Lam, Bonnie Yin Ka; Wong, Ka Sing; Mok, Vincent; Chu, Winnie C.W.; Leung, Thomas

doi:10.1136/jnnp-2018-319104

Cited by 15 publications

(18 citation statements)

References 37 publications

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“…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.…”

Section: Discussionsupporting

confidence: 69%

“…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.…”

Section: Discussioncontrasting

confidence: 60%

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

Wilson¹,

Ambler²,

Lee³

et al. 2019

The Lancet Neurology

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158

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Summary 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 10...

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Section: Discussionsupporting

confidence: 69%

Section: Discussioncontrasting

confidence: 60%

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

Wilson¹,

Ambler²,

Lee³

et al. 2019

The Lancet Neurology

Self Cite

158

106

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“…We performed both internal validation using bootstrapping and internal-external cross-validation, in accordance with TRIPOD guidelines and expert recommendations. 22,24 While we omitted some potentially clinically relevant variables from our model due to missing data, additional analyses suggested this did not reduce model performance.…”

Section: Discussionmentioning

confidence: 99%

“…We internally validated our models using bootstrapping. 20 As an additional test of model performance, we did internal-external cross validation, 21,22 using five folds consisting of whole cohorts, repeated 20 times to reduce variance. We quantified discrimination using Harrell's cindex, and calibration through the calibration slope.…”

Section: Statistical Analysesmentioning

confidence: 99%

Development of imaging-based risk scores for prediction of intracranial haemorrhage and ischaemic stroke in patients taking antithrombotic therapy after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies

Best¹,

Ambler²,

Wilson³

et al. 2021

The Lancet Neurology

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Research in context panel: 445Identifying people at highest risk of ICH may facilitate timely and accurate prognostication to allow mitigation of reversible risk factors for bleeding (e.g. intensive blood pressure control), and selection of participants for clinical trials. While more complex combinations of clinical, biochemical, and radiological markers might further improve stroke risk prediction, balancing accuracy with simplicity will remain important.

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“…However, devastating symptomatic intracerebral hemorrhage is an especially serious complication for Asian patients who are prone to bleeding. Several observational studies and meta-analyses [ 19 – 21 ] suggest a link between CMBs on MRI and increased future intracerebral hemorrhage risk in patients with atrial fibrillation. The CROMIS-2 study, a multicenter prospective observational cohort study, that enrolled patients with atrial fibrillation and recent stroke or TIA treated with WF or DOACs, showed that the presence of CMBs was independently associated with symptomatic intracerebral hemorrhage [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Oral anticoagulant use and the development of new cerebral microbleeds in cardioembolic stroke patients with atrial fibrillation

2020

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Objective Cerebral microbleeds (CMBs) are a magnetic resonance imaging (MRI) marker for cerebral small vessel disease. Existing CMBs and those that newly develop are associated with the risks of stroke incidence and recurrence. The purpose of the present study was to investigate the association of oral anticoagulant (OAC) use and the development of new CMBs in cardioembolic stroke patients with atrial fibrillation. Subjects and methods We prospectively followed cardioembolic stroke patients with atrial fibrillation who had been hospitalized in the stroke center of our hospital, had been prescribed anticoagulants at discharge, and underwent repeated brain MRI with an interval of at least one year from the baseline MRI. Assessing the presence, number and location of CMBs using T2*-weighted gradient-recalled echo MRI, we used logistic regression models to investigate the associations between OAC use and the incidence of new CMBs. We also examined associations of subsequent stroke with OACs and CMBs during the follow-up. Results A total of 81 patients, consisting of 45 patients receiving direct oral anticoagulants (DOACs) and 36 patients receiving warfarin (WF), were analyzed in the present study. Baseline CMBs were observed in 19/81 patients (23.5%) and new CMBs in 18/81 patients (22.2%) on follow-up MRI (median interval, 34 months). Of the 31 new CMBs, 25 (80.6%) developed in the lobar location and 6 (19.4%) in the deep or infratentorial location. New CMBs occurred in 4 patients (10.0%) taking DOACs　alone, in 10 patients (35.7%) taking WF alone, in 3 patients (37.5%) taking WF plus antiplatelet agents and in 1 patient (20.0%) taking DOAC plus antiplatelet agent. Regarding location, the new CMBs were the lobar type in 7 of the 10 patients taking WF alone, as well as in 3 of the 4 patients taking DOACs alone. In multivariate analysis, the presence of CMBs at baseline and WF use (vs. DOAC use) were associated with new CMBs (CMB presence at baseline: OR 4.16, 95% CI 1.19–14.44; WF use: OR 3.38, 95% CI 1.02–11.42). The presence of ≥ 2 CMBs at baseline was related to a higher risk of subsequent stroke (OR 7.25, 95% CI 1.01–52.35, P = 0.048). Conclusion Our findings suggest that DOAC compared with WF use at discharge is associated with a lower incidence of new CMBs in cardioembolic stroke patients with atrial fibrillation. Further prospective studies in the clinical setting are needed to confirm our exploratory data.

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Risk of intracerebral haemorrhage in Chinese patients with atrial fibrillation on warfarin with cerebral microbleeds: the IPAAC-Warfarin study

Cited by 15 publications

References 37 publications

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

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

Development of imaging-based risk scores for prediction of intracranial haemorrhage and ischaemic stroke in patients taking antithrombotic therapy after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies

Oral anticoagulant use and the development of new cerebral microbleeds in cardioembolic stroke patients with atrial fibrillation

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