Abstract
SummaryBackgroundCerebral microbleeds are a potential neuroimaging biomarker of cerebral small vessel diseases that are prone to intracranial bleeding. We aimed to determine whether presence of cerebral microbleeds can identify patients at high risk of symptomatic intracranial haemorrhage when anticoagulated for atrial fibrillation after recent ischaemic stroke or transient ischaemic attack.MethodsOur observational, multicentre, prospective inception cohort study recruited adults aged 18 years or older from 79 hospitals in the UK and one in the Netherlands with atrial fibrillation and recent acute ischaemic stroke or transient ischaemic attack, treated with a vitamin K antagonist or direct oral anticoagulant, and followed up for 24 months using general practitioner and patient postal questionnaires, telephone interviews, hospital visits, and National Health Service digital data on hospital admissions or death. We excluded patients if they could not undergo MRI, had a definite contraindication to anticoagulation, or had previously received therapeutic anticoagulation. The primary outcome was symptomatic intracranial haemorrhage occurring at any time before the final follow-up at 24 months. The log-rank test was used to compare rates of intracranial haemorrhage between those with and without cerebral microbleeds. We developed two prediction models using Cox regression: first, including all predictors associated with intracranial haemorrhage at the 20% level in univariable analysis; and second, including cerebral microbleed presence and HAS-BLED score. We then compared these with the HAS-BLED score alone. This study is registered with ClinicalTrials.gov, number NCT02513316.FindingsBetween Aug 4, 2011, and July 31, 2015, we recruited 1490 participants of whom follow-up data were available for 1447 (97%), over a mean period of 850 days (SD 373; 3366 patient-years). The symptomatic intracranial haemorrhage rate in patients with cerebral microbleeds was 9·8 per 1000 patient-years (95% CI 4·0–20·3) compared with 2·6 per 1000 patient-years (95% CI 1·1–5·4) in those without cerebral microbleeds (adjusted hazard ratio 3·67, 95% CI 1·27–10·60). Compared with the HAS-BLED score alone (C-index 0·41, 95% CI 0·29–0·53), models including cerebral microbleeds and HAS-BLED (0·66, 0·53–0·80) and cerebral microbleeds, diabetes, anticoagulant type, and HAS-BLED (0·74, 0·60–0·88) predicted symptomatic intracranial haemorrhage significantly better (difference in C-index 0·25, 95% CI 0·07–0·43, p=0·0065; and 0·33, 0·14–0·51, p=0·00059, respectively).InterpretationIn patients with atrial fibrillation anticoagulated after recent ischaemic stroke or transient ischaemic attack, cerebral microbleed presence is independently associated with symptomatic intracranial haemorrhage risk and could be used to inform anticoagulation decisions. Large-scale collaborative observational cohort analyses are needed to refine and validate intracranial haemorrhage risk scores incorporating cerebral microbleeds to identify patients at risk of net harm from oral anticoagulation.FundingThe Stroke Association and the British Heart Foundation.
Highlights
Atrial fibrillation increases the risk of ischaemic stroke by five times.[1]
Oral anticoagulation with either vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) is indicated because they reduce the risk of ischaemic stroke by about two thirds, with only a minimal increase in extracranial haemorrhage.[2,3]
We developed and internally validated a simple risk prediction score for intracranial haemorrhage, showing for the first time that the inclusion of cerebral microbleed presence as a neuroimaging biomarker improves the predictive value of a commonly used bleeding risk score based on clinical data alone
Summary
A devastating and unpredictable complication of oral anticoagulation is symptomatic intracranial haemorrhage, which has 42% in-hospital mortality and causes substantial disability in survivors.[4] There is an unmet clinical need to reliably predict the risk of intracranial haemorrhage and to differentiate this from the risk of ischaemic stroke, to allow clinicians to assess. Royal Hallamshire Hospital, Sheffield Teaching Hospitals Foundation Trust, Sheffield, UK (K Harkness FRCP); Department of Neurology, Royal Berkshire. United Hospital, Bath, UK (L J Shaw FRCP); Department of Clinical Neurosciences, Addenbrookes Hospital, Cambridge, UK (E Warburton FRCP); and Institute of Neuroscience & Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK (Prof K W Muir FRCP). Correspondence to: Prof David J Werring, UCL Stroke Research Centre, Department of Brain Repair and Rehabilitation, See Online for appendix
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