title: A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon.
abstract: BACKGROUND
  Observational evidence suggests that the use of a genotype-guided dosing algorithm may increase the effectiveness and safety of acenocoumarol and phenprocoumon therapy.
  
  
  METHODS
  We conducted two single-blind, randomized trials comparing a genotype-guided dosing algorithm that included clinical variables and genotyping for CYP2C9 and VKORC1 with a dosing algorithm that included only clinical variables, for the initiation of acenocoumarol or phenprocoumon treatment in patients with atrial fibrillation or venous thromboembolism. The primary outcome was the percentage of time in the target range for the international normalized ratio (INR; target range, 2.0 to 3.0) in the 12-week period after the initiation of therapy. Owing to low enrollment, the two trials were combined for analysis. The primary outcome was assessed in patients who remained in the trial for at least 10 weeks.
  
  
  RESULTS
  A total of 548 patients were enrolled (273 patients in the genotype-guided group and 275 in the control group). The follow-up was at least 10 weeks for 239 patients in the genotype-guided group and 245 in the control group. The percentage of time in the therapeutic INR range was 61.6% for patients receiving genotype-guided dosing and 60.2% for those receiving clinically guided dosing (P=0.52). There were no significant differences between the two groups for several secondary outcomes. The percentage of time in the therapeutic range during the first 4 weeks after the initiation of treatment in the two groups was 52.8% and 47.5% (P=0.02), respectively. There were no significant differences with respect to the incidence of bleeding or thromboembolic events.
  
  
  CONCLUSIONS
  Genotype-guided dosing of acenocoumarol or phenprocoumon did not improve the percentage of time in the therapeutic INR range during the 12 weeks after the initiation of therapy. (Funded by the European Commission Seventh Framework Programme and others; EU-PACT ClinicalTrials.gov numbers, NCT01119261 and NCT01119274.).
authors.affiliation: The authors' affiliations are listed in the Appendix.
authors.forename: Talitha I
authors.initials: TI
authors.lastname: Verhoef
authors.forename: Georgia
authors.initials: G
authors.lastname: Ragia
authors.forename: Anthonius
authors.initials: A
authors.lastname: de Boer
authors.forename: Rita
authors.initials: R
authors.lastname: Barallon
authors.forename: Genovefa
authors.initials: G
authors.lastname: Kolovou
authors.forename: Vana
authors.initials: V
authors.lastname: Kolovou
authors.forename: Stavros
authors.initials: S
authors.lastname: Konstantinides
authors.forename: Saskia
authors.initials: S
authors.lastname: Le Cessie
authors.forename: Efstratios
authors.initials: E
authors.lastname: Maltezos
authors.forename: Felix J M
authors.initials: FJ
authors.lastname: van der Meer
authors.forename: William K
authors.initials: WK
authors.lastname: Redekop
authors.forename: Mary
authors.initials: M
authors.lastname: Remkes
authors.forename: Frits R
authors.initials: FR
authors.lastname: Rosendaal
authors.forename: Rianne M F
authors.initials: RM
authors.lastname: van Schie
authors.forename: Anna
authors.initials: A
authors.lastname: Tavridou
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tziakas
authors.forename: Mia
authors.initials: M
authors.lastname: Wadelius
authors.forename: Vangelis G
authors.initials: VG
authors.lastname: Manolopoulos
authors.forename: Anke H
authors.initials: AH
authors.lastname: Maitland-van der Zee
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage*; D000368:Aged; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010644:Phenprocoumon / Q000008:administration & dosage*; D016037:Single-Blind Method; D013923:Thromboembolism / Q000139:chemically induced; D017211:Treatment Failure; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*
chemical_list: D000925:Anticoagulants; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol; D010644:Phenprocoumon