title: The Clinical Relevance of Microbleeds in Stroke study (CROMIS-2): rationale, design, and methods.
abstract: OBJECTIVE
  The increasing use of oral anticoagulants, mostly to prevent ischemic stroke due to atrial fibrillation in an ageing population, has been associated with a fivefold increased incidence of oral anticoagulant-associated intracerebral hemorrhage: a rare, serious, and unpredictable complication. We hypothesize that cerebral microbleeds and other markers of cerebral small vessel disease on magnetic resonance imaging, and genetic polymorphisms (e.g. influencing cerebral small vessel integrity or anticoagulation stability), are associated with an increased risk of oral anticoagulant-associated intracerebral hemorrhage, with potential to improve risk prediction.
  
  
  OBJECTIVE
  (1) To determine the incidence, clinical, radiological, and genetic associations of oral anticoagulant-associated intracerebral hemorrhage in a prospective, multicentre cohort study of patients with atrial fibrillation-related ischemic stroke or transient ischemic attack started on oral anticoagulants; (2) To investigate characteristics of oral anticoagulant-associated intracerebral hemorrhage compared with non-oral anticoagulants related intracerebral hemorrhage in a prospective study.
  
  
  METHODS
  Study 1: Prospective, multicentre, inception cohort study of 1425 adults started on oral anticoagulants (including vitamin K antagonists and the nonvitamin K oral anticoagulants) after recent ischemic stroke and concurrent atrial fibrillation. Participants will have standardized brain magnetic resonance imaging (including a T2*-weighted gradient-recalled echo sequence) and DNA sample collection at baseline, with two-year follow-up by postal questionnaire and medical records surveillance for symptomatic intracranial hemorrhage, other serious vascular events, and death. We will compare the rates of symptomatic intracranial hemorrhage (primary outcome; subclassified as intracerebral, subdural, extradural, intraventricular), other vascular events, and death (secondary outcomes) in participants with one or more cerebral microbleeds to the rates in those without cerebral microbleeds.
  
  
  METHODS
  Prospective case-control study of oral anticoagulant-associated intracerebral hemorrhage compared with non-oral anticoagulant-associated intracerebral hemorrhage to investigate genetic, clinical, and radiological associations with oral anticoagulant-associated intracerebral hemorrhage. In participants with intracerebral hemorrhage (including at least 300 with oral anticoagulant-associated intracerebral hemorrhage), we will collect a DNA sample, standardized clinical data and routine brain imaging (magnetic resonance imaging or computed tomography), and information on functional outcome.
  
  
  OBJECTIVE
  We will identify the factors associated with increased intracranial hemorrhage risk after oral anticoagulants for secondary prevention after ischemic stroke due to atrial fibrillation. We will determine clinical, radiological and genetic factors, and clinical outcomes associated with oral anticoagulant-associated intracerebral hemorrhage.
authors.affiliation: UCL Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Charidimou
authors.affiliation: UCL Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Duncan
authors.initials: D
authors.lastname: Wilson
authors.affiliation: UCL Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Shakeshaft
authors.affiliation: Department of Statistical Science, UCL, London, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Ambler
authors.affiliation: Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: White
authors.affiliation: University College London Hospitals NHS Foundation Trust, London, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Cohen
authors.affiliation: Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, UK.|Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, UK.
authors.forename: Tarek
authors.initials: T
authors.lastname: Yousry
authors.affiliation: Division of Clinical Neurosciences, Centre for Clinical Brain Sciences, School of Clinical Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Rustam
authors.initials: R
authors.lastname: Al-Shahi Salman
authors.affiliation: University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK.
authors.forename: Gregory
authors.initials: G
authors.lastname: Lip
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, UK.|University College London Hospitals NHS Foundation Trust, London, UK.
authors.forename: Hans R
authors.initials: HR
authors.lastname: Jäger
authors.affiliation: UCL Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Martin M
authors.initials: MM
authors.lastname: Brown
authors.affiliation: UCL Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Werring
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage; D001921:Brain / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D020300:Intracranial Hemorrhages / Q000453:epidemiology* / Q000209:etiology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D063868:Patient Outcome Assessment; D012307:Risk Factors; D020521:Stroke / Q000150:complications / Q000188:drug therapy / Q000453:epidemiology* / Q000235:genetics; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000925:Anticoagulants
keywords: atrial fibrillation; cerebral microbleeds; cerebral small vessel disease; intracerebral hemorrhage; oral anticoagulants