title: Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation.
abstract: BACKGROUND
  Pharmacogenetic-guided dosing of warfarin is a promising application of "personalized medicine" but has not been adequately tested in randomized trials.
  
  
  RESULTS
  Consenting patients (n=206) being initiated on warfarin were randomized to pharmacogenetic-guided or standard dosing. Buccal swab DNA was genotyped for CYP2C9 *2 and CYP2C9 *3 and VKORC1C1173T with a rapid assay. Standard dosing followed an empirical protocol, whereas pharmacogenetic-guided dosing followed a regression equation including the 3 genetic variants and age, sex, and weight. Prothrombin time international normalized ratio (INR) was measured routinely on days 0, 3, 5, 8, 21, 60, and 90. A research pharmacist unblinded to treatment strategy managed dose adjustments. Patients were followed up for up to 3 months. Pharmacogenetic-guided predicted doses more accurately approximated stable doses (P<0.001), resulting in smaller (P=0.002) and fewer (P=0.03) dosing changes and INRs (P=0.06). However, percent out-of-range INRs (pharmacogenetic = 30.7%, standard = 33.1%), the primary end point, did not differ significantly between arms. Despite this, when restricted to wild-type patients (who required larger doses; P=0.001) and multiple variant carriers (who required smaller doses; P<0.001) in exploratory analyses, results (pharmacogenetic = 29%, standard = 39%) achieved nominal significance (P=0.03). Multiple variant allele carriers were at increased risk of an INR of > or = 4 (P=0.03).
  
  
  CONCLUSIONS
  An algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation. Despite this, the primary end point of a reduction in out-of-range INRs was not achieved. In subset analyses, pharmacogenetic guidance showed promise for wild-type and multiple variant genotypes.
authors.affiliation: Cardiovascular Department, LDS Hospital, Intermountain Healthcare, Salt Lake City, UT, USA. jeffrey.anderson@intermountainmail.org
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Anderson
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Horne
authors.forename: Scott M
authors.initials: SM
authors.lastname: Stevens
authors.forename: Amanda S
authors.initials: AS
authors.lastname: Grove
authors.forename: Stephanie
authors.initials: S
authors.lastname: Barton
authors.forename: Zachery P
authors.initials: ZP
authors.lastname: Nicholas
authors.forename: Samera F S
authors.initials: SF
authors.lastname: Kahn
authors.forename: Heidi T
authors.initials: HT
authors.lastname: May
authors.forename: Kent M
authors.initials: KM
authors.lastname: Samuelson
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Muhlestein
authors.forename: John F
authors.initials: JF
authors.lastname: Carlquist
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000925:Anticoagulants / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D054796:Drug Dosage Calculations; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods*; D016896:Treatment Outcome; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D064417:Vitamin K Epoxide Reductases