title: Off-Label Dosing of Non-Vitamin K Antagonist Oral Anticoagulants and Adverse Outcomes: The ORBIT-AF II Registry.
abstract: BACKGROUND
  Although non-vitamin K antagonist oral anticoagulants (NOACs) do not require frequent laboratory monitoring, each compound requires dose adjustments on the basis of certain clinical criteria.
  
  
  OBJECTIVE
  This study assessed the frequency of off-label NOAC doses among AF patients and the associations between off-label dose therapy and clinical outcomes in community practice.
  
  
  METHODS
  We evaluated 5,738 patients treated with a NOAC at 242 ORBIT-AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation phase II) sites. NOAC doses were classified as either underdosed or overdosed, consistent with Food and Drug Administration labeling. Longitudinal outcomes (median follow-up: 0.99 years) included stroke or systemic embolism, myocardial infarction, major bleeding (International Society of Thrombosis and Haemostasis criteria), cause-specific hospitalization, and all-cause mortality.
  
  
  RESULTS
  Overall, 541 NOAC-treated patients (9.4%) were underdosed, 197 were overdosed (3.4%), and 5,000 were dosed according to U.S. labeling (87%). Compared with patients receiving the recommended dose, those who were receiving off-label doses were older (median: 79 and 80 years of age vs. 70 years of age, respectively; p < 0.0001), more likely female (48% and 67% vs. 40%, respectively; p < 0.0001), less likely to be treated by an electrophysiologist (18% and 19% vs. 27%, respectively; p < 0.0001), and had higher CHA2DS2-VASc scores (96% and 97% ≥2 vs. 86%, respectively; p < 0.0001) and higher ORBIT bleeding scores (25% and 31% >4 vs. 11%, respectively; p < 0.0001). After dose adjustment, NOAC overdosing was associated with increased all-cause mortality compared with recommended doses (adjusted hazard ratio: 1.91; 95% confidence interval [CI]: 1.02 to 3.60; p = 0.04). Underdosing was associated with increased cardiovascular hospitalization (adjusted hazard ratio: 1.26; 95% CI: 1.07 to 1.50; p = 0.007).
  
  
  CONCLUSIONS
  A significant minority (almost 1 in 8) of U.S. patients in the community received NOAC doses inconsistent with labeling. NOAC over- and underdosing are associated with increased risk for adverse events. (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II [ORBIT-AF II]; NCT01701817).
authors.affiliation: Division of Cardiovascular Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah; Department of Medicine, Duke University Medical Center, Durham, North Carolina; Duke Clinical Research Institute, Durham, North Carolina. Electronic address: benjamin.steinberg@hsc.utah.edu.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Steinberg
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Peter
authors.initials: P
authors.lastname: Shrader
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Laine
authors.initials: L
authors.lastname: Thomas
authors.affiliation: Department of Medicine, Hofstra Northwell School of Medicine, Long Island, New York.
authors.forename: Jack
authors.initials: J
authors.lastname: Ansell
authors.affiliation: Ahmanson-UCLA Cardiomyopathy Center, University of California Los Angeles Division of Cardiology, Los Angeles, California.
authors.forename: Gregg C
authors.initials: GC
authors.lastname: Fonarow
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Gersh
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Kowey
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Palo Alto, California.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Mahaffey
authors.affiliation: Department of Medicine, Penn State University School of Medicine, Hershey, Pennsylvania.
authors.forename: Gerald
authors.initials: G
authors.lastname: Naccarelli
authors.affiliation: Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York.
authors.forename: James
authors.initials: J
authors.lastname: Reiffel
authors.affiliation: Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Singer
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina; Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Peterson
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina; Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Piccini
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage*; D001281:Atrial Fibrillation / Q000150:complications / Q000188:drug therapy*; D002423:Cause of Death / Q000639:trends; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D056687:Off-Label Use / Q000706:statistics & numerical data*; D012042:Registries; D012189:Retrospective Studies; D020521:Stroke / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control*; D015996:Survival Rate / Q000639:trends; D014481:United States / Q000453:epidemiology; D014812:Vitamin K
chemical_list: D000925:Anticoagulants; D014812:Vitamin K
keywords: apixaban; atrial fibrillation; dabigatran; off-label use; outcomes; rivaroxaban