title: Antithrombotic drug use, cerebral microbleeds, and intracerebral hemorrhage: a systematic review of published and unpublished studies.
abstract: OBJECTIVE
  Cerebral microbleeds (MB) are potential risk factors for intracerebral hemorrhage (ICH), but it is unclear if they are a contraindication to using antithrombotic drugs. Insights could be gained by pooling data on MB frequency stratified by antithrombotic use in cohorts with ICH and ischemic stroke (IS)/transient ischemic attack (TIA).
  
  
  METHODS
  We performed a systematic review of published and unpublished data from cohorts with stroke or TIA to compare the presence of MB in: (1) antithrombotic users vs nonantithrombotic users with ICH; (2) antithrombotic users vs nonusers with IS/TIA; and (3) ICH vs ischemic events stratified by antithrombotic use. We also analyzed published and unpublished follow-up data to determine the risk of ICH in antithrombotic users with MB.
  
  
  RESULTS
  In a pooled analysis of 1460 ICH and 3817 IS/TIA, MB were more frequent in ICH vs IS/TIA in all treatment groups, but the excess increased from 2.8 (odds ratio; range, 2.3-3.5) in nonantithrombotic users to 5.7 (range, 3.4-9.7) in antiplatelet users and 8.0 (range, 3.5-17.8) in warfarin users (P difference=0.01). There was also an excess of MB in warfarin users vs nonusers with ICH (OR, 2.7; 95% CI, 1.6-4.4; P<0.001) but none in warfarin users with IS/TIA (OR, 1.3; 95% CI, 0.9-1.7; P=0.33; P difference=0.01). There was a smaller excess of MB in antiplatelet users vs nonusers with ICH (OR, 1.7; 95% CI, 1.3-2.3; P<0.001), but findings were similar for antiplatelet users with IS/TIA (OR, 1.4; 95% CI, 1.2-1.7; P<0.001; P difference=0.25). In pooled follow-up data for 768 antithrombotic users, presence of MB at baseline was associated with a substantially increased risk of subsequent ICH (OR, 12.1; 95% CI, 3.4-42.5; P<0.001).
  
  
  CONCLUSIONS
  The excess of MB in warfarin users with ICH compared to other groups suggests that MB increase the risk of warfarin-associated ICH. Limited prospective data corroborate these findings, but larger prospective studies are urgently required.
authors.affiliation: Stroke Prevention Research Unit, University Department of Clinical Neurology, Level 6, West Wing, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU. caroline.lovelock@clneuro.ox.ac.uk
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Lovelock
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cordonnier
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Naka
authors.forename: Rustam
authors.initials: R
authors.lastname: Al-Shahi Salman
authors.forename: Cathie L M
authors.initials: CL
authors.lastname: Sudlow
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Sorimachi
authors.forename: David J
authors.initials: DJ
authors.lastname: Werring
authors.forename: Simone M
authors.initials: SM
authors.lastname: Gregoire
authors.forename: Toshio
authors.initials: T
authors.lastname: Imaizumi
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Dennis
authors.initials: D
authors.lastname: Briley
authors.forename: Peter M
authors.initials: PM
authors.lastname: Rothwell
mesh_terms: D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects; D002545:Brain Ischemia / Q000139:chemically induced; D002543:Cerebral Hemorrhage / Q000139:chemically induced*; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D008297:Male; D012307:Risk Factors; D020521:Stroke / Q000139:chemically induced; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000925:Anticoagulants; D005343:Fibrinolytic Agents; D014859:Warfarin