title: Meta-analysis to assess the quality of international normalized ratio control and associated outcomes in venous thromboembolism patients.
abstract: BACKGROUND
  Patients with venous thromboembolism (VTE) frequently require vitamin K antagonists (VKAs) to prevent recurrent events, but their use increases hemorrhage risk. We performed a meta-analysis to assess the quality of international normalized ratio (INR) control, identify study-level predictors of poor control and to examine the relationship between INR control and adverse outcomes in VTE patients.
  
  
  METHODS
  We searched bibliographic databases (1990-June 2013) for studies of VTE patients receiving adjusted-dose VKAs that reported time in range (2.0-3.0) or proportion of INRs in range and/or reported INR measurements coinciding with thromboembolic or hemorrhagic events. Meta-analysis and meta-regression analysis was performed.
  
  
  RESULTS
  Upon meta-analysis, studies found 59% (95%CI: 54-64%) of INRs measured and 61% (95%CI: 59-63%) of the time patients were treated were spent outside the target range of 2.0-3.0; with a tendency for under- versus over-anticoagulation. Moreover, this poor INR control resulted in a greater chance of recurrent VTE (beta-coefficient=-0.46, p=0.01) and major bleeding (beta-coefficient=-0.30, p=0.02). Patients with an INR<2.0 made up 58% (95%CI: 39-77%) of VTE cases, while those with an INR>3.0 made up 48% (95%CI: 34-61%) of major hemorrhage cases. Upon meta-regression, being VKA-naïve (-14%, p=0.04) and treated in the community (-7%, p<0.001) were associated with less time in range, while being treated in Europe/United Kingdom (compared to North America) was associated with (11%, p=0.003) greater time.
  
  
  CONCLUSIONS
  Strategies to improve INR control or alternative anticoagulants, including the newer oral agents, should be widely implemented in VTE patients to reduce the rate of recurrent events and bleeding.
authors.affiliation: University of Connecticut School of Pharmacy, Department of Pharmacy Practice, 69N Eagleville Road, Storrs, CT, 06269-3092, USA; Hartford Hospital Division of Cardiology, 80 Seymour Street, Hartford, CT, 06102-5037, USA. Electronic address: Elizabeth.Mearns@hhchealth.org.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Mearns
authors.affiliation: University of Connecticut School of Pharmacy, Department of Pharmacy Practice, 69N Eagleville Road, Storrs, CT, 06269-3092, USA; Hartford Hospital Division of Cardiology, 80 Seymour Street, Hartford, CT, 06102-5037, USA. Electronic address: Christine.Kohn@hhchealth.org.
authors.forename: Christine G
authors.initials: CG
authors.lastname: Kohn
authors.affiliation: University of Connecticut School of Pharmacy, Department of Pharmacy Practice, 69N Eagleville Road, Storrs, CT, 06269-3092, USA. Electronic address: Ju-Sung.Song@uconn.edu.
authors.forename: Ju-Sung
authors.initials: JS
authors.lastname: Song
authors.affiliation: University of Connecticut School of Pharmacy, Department of Pharmacy Practice, 69N Eagleville Road, Storrs, CT, 06269-3092, USA. Electronic address: Jessica.Hawthorne@uconn.edu.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hawthorne
authors.affiliation: University of Connecticut School of Pharmacy, Department of Pharmacy Practice, 69N Eagleville Road, Storrs, CT, 06269-3092, USA. Electronic address: Joy.Meng@uconn.edu.
authors.forename: Joy
authors.initials: J
authors.lastname: Meng
authors.affiliation: University of Connecticut School of Pharmacy, Department of Pharmacy Practice, 69N Eagleville Road, Storrs, CT, 06269-3092, USA; Hartford Hospital Division of Cardiology, 80 Seymour Street, Hartford, CT, 06102-5037, USA.
authors.forename: C Michael
authors.initials: CM
authors.lastname: White
authors.affiliation: Janssen Scientific Affairs, LLC, Raritan, NJ, USA. Electronic address: MRaut1@its.jnj.com.
authors.forename: Monika K
authors.initials: MK
authors.lastname: Raut
authors.affiliation: Janssen Scientific Affairs, LLC, Raritan, NJ, USA. Electronic address: JSchein@its.jnj.com.
authors.forename: Jeff R
authors.initials: JR
authors.lastname: Schein
authors.affiliation: University of Connecticut School of Pharmacy, Department of Pharmacy Practice, 69N Eagleville Road, Storrs, CT, 06269-3092, USA; Hartford Hospital Division of Cardiology, 80 Seymour Street, Hartford, CT, 06102-5037, USA. Electronic address: Craig.Coleman@hhchealth.org.
authors.forename: Craig I
authors.initials: CI
authors.lastname: Coleman
mesh_terms: D000925:Anticoagulants / Q000009:adverse effects / Q000627:therapeutic use*; D016903:Drug Monitoring; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D019934:International Normalized Ratio; D016896:Treatment Outcome; D054556:Venous Thromboembolism / Q000175:diagnosis / Q000188:drug therapy*; D014812:Vitamin K / Q000037:antagonists & inhibitors*
chemical_list: D000925:Anticoagulants; D014812:Vitamin K
keywords: Anticoagulation; International Normalized Ratio; Venous Thromboembolism; Vitamin K Antagonist