title: Anticoagulation intensity and outcomes among patients prescribed oral anticoagulant therapy: a systematic review and meta-analysis.
abstract: BACKGROUND
  Patients taking oral anticoagulant therapy balance the risks of hemorrhage and thromboembolism. We sought to determine the association between anticoagulation intensity and the risk of hemorrhagic and thromboembolic events. We also sought to determine how under-or overanticoagulation would influence patient outcomes.
  
  
  METHODS
  We reviewed the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and CINAHL databases to identify studies involving patients taking anticoagulants that reported person-years of observation and the number of hemorrhages or thromboemboli in 3 or more discrete ranges of international normalized ratios. We estimated the overall relative and absolute risks of events specific to anticoagulation intensity.
  
  
  RESULTS
  We included 19 studies. The risk of hemorrhage increased significantly at high international normalized ratios. Compared with the therapeutic ratio of 2-3, the relative risk (RR) of hemorrhage (and 95% confidence intervals [CIs]) were 2.7 (1.8-3.9; p < 0.01) at a ratio of 3-5 and 21.8 (12.1-39.4; p < 0.01) at a ratio greater than 5. The risk of thromboemboli increased significantly at ratios less than 2, with a relative risk of 3.5 (95% CI 2.8-4.4; p < 0.01). The risk of hemorrhagic or thromboembolic events was lower at ratios of 3-5 (RR 1.8, 95% CI 1.2-2.6) than at ratios of less than 2 (RR 2.4, 95% CI 1.9-3.1; p = 0.10). We found that a ratio of 2-3 had the lowest absolute risk (AR) of events (AR 4.3%/yr, 95% CI 3.0%-6.3%).
  
  
  CONCLUSIONS
  The risks of hemorrhage and thromboemboli are minimized at international normalized ratios of 2-3. Ratios that are moderately higher than this therapeutic range appear safe and more effective than subtherapeutic ratios.
authors.affiliation: Department of Medicine, University of Ottawa, and the Clinical Epidemiology Program, Ottawa Health Research Institute, Ottawa, Ont.
authors.forename: Natalie
authors.initials: N
authors.lastname: Oake
authors.forename: Alison
authors.initials: A
authors.lastname: Jennings
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Forster
authors.forename: Dean
authors.initials: D
authors.lastname: Fergusson
authors.forename: Steve
authors.initials: S
authors.lastname: Doucette
authors.forename: Carl
authors.initials: C
authors.lastname: van Walraven
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D011307:Drug Prescriptions; D006470:Hemorrhage / Q000517:prevention & control*; D006801:Humans; D019934:International Normalized Ratio; D011379:Prognosis; D013923:Thromboembolism / Q000097:blood / Q000188:drug therapy*
chemical_list: D000925:Anticoagulants