title: A randomized controlled trial of genotype-based Coumadin initiation.
abstract: OBJECTIVE
  A randomized controlled trial was conducted in patients initiating warfarin to determine whether algorithms that incorporate genotypes affecting warfarin metabolism and function, and Vitamin K metabolism improve prediction of therapeutic warfarin dose and anticoagulation management.
  
  
  METHODS
  A total of 230 patients were randomized to either a clinical arm where dosing algorithms considered only clinical information or an interventional arm where dosing algorithms used clinical and genotypic variables (CYP2C9, CYP4F2, and VKORC1). Subjects in the interventional arm were genotyped within 5 hours, and the initial dose was informed by genotype. Primary endpoints were absolute prediction error relative to therapeutic dose, and time in therapeutic target range during the first 14 days. Secondary endpoints included time to stable dose in therapeutic range, time to first international normalization ratio >4, and warfarin-related adverse events.
  
  
  RESULTS
  The model including genetics more accurately identified therapeutic dose twice as often as the clinical model (65.3% vs. 34.7%) (P < 0.0001). Patients in the interventional arm did not achieve greater time in therapeutic range. Study arms were similar regarding time to international normalization ratio >4 and adverse events.
  
  
  CONCLUSIONS
  Genotype-informed dosing clearly improved prediction of therapeutic dose beyond that available with clinical parameters. Genetic information did not affect time in therapeutic target range during the first 14 days of therapy. Current management practices with the vagaries in dose adjustment after warfarin initiation exert a strong influence on traditional clinical outcomes.
authors.affiliation: Department of Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin.
authors.forename: James K
authors.initials: JK
authors.lastname: Burmester
authors.forename: Richard L
authors.initials: RL
authors.lastname: Berg
authors.forename: Steven H
authors.initials: SH
authors.lastname: Yale
authors.forename: Carla M
authors.initials: CM
authors.lastname: Rottscheit
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Glurich
authors.forename: John R
authors.initials: JR
authors.lastname: Schmelzer
authors.forename: Michael D
authors.initials: MD
authors.lastname: Caldwell
mesh_terms: D000328:Adult; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D004305:Dose-Response Relationship, Drug; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D014812:Vitamin K / Q000378:metabolism*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D014812:Vitamin K; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases