title: A randomized trial of genotype-guided dosing of warfarin.
abstract: BACKGROUND
  The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy.
  
  
  METHODS
  We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation.
  
  
  RESULTS
  A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR ≥4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001).
  
  
  CONCLUSIONS
  Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. (Funded by the European Commission Seventh Framework Programme and others; ClinicalTrials.gov number, NCT01119300.).
authors.affiliation: From the University of Liverpool (M.P., G.B., A.L.J., C.H.T., J.E.Z., P.R.W.) and Royal Liverpool and Broadgreen University Hospital National Health Service (NHS) Trust (M.P., C.H.T.), Liverpool, Whiston Hospital, Prescot (T.N.), and Newcastle upon Tyne NHS Trust (P.K.) and Newcastle University (J.B.L., A.K.D., P.A., F.K.), Newcastle upon Tyne - all in the United Kingdom; Uppsala University, Department of Medical Sciences (N.E., C.C., H.K., M.W.), Uppsala Clinical Research Center (N.E.) and Uppsala University Hospital (C.C., B.W., M.W.), Uppsala, and Enköping Hospital, Enköping (C.S.) - all in Sweden; and Utrecht University, Utrecht, the Netherlands (A.H.M.Z.).
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: Girvan
authors.initials: G
authors.lastname: Burnside
authors.forename: Niclas
authors.initials: N
authors.lastname: Eriksson
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Jorgensen
authors.forename: Cheng Hock
authors.initials: CH
authors.lastname: Toh
authors.forename: Toby
authors.initials: T
authors.lastname: Nicholson
authors.forename: Patrick
authors.initials: P
authors.lastname: Kesteven
authors.forename: Christina
authors.initials: C
authors.lastname: Christersson
authors.forename: Bengt
authors.initials: B
authors.lastname: Wahlström
authors.forename: Christina
authors.initials: C
authors.lastname: Stafberg
authors.forename: J Eunice
authors.initials: JE
authors.lastname: Zhang
authors.forename: Julian B
authors.initials: JB
authors.lastname: Leathart
authors.forename: Hugo
authors.initials: H
authors.lastname: Kohnke
authors.forename: Anke H
authors.initials: AH
authors.lastname: Maitland-van der Zee
authors.forename: Paula R
authors.initials: PR
authors.lastname: Williamson
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
authors.forename: Peter
authors.initials: P
authors.lastname: Avery
authors.forename: Farhad
authors.initials: F
authors.lastname: Kamali
authors.forename: Mia
authors.initials: M
authors.lastname: Wadelius
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001281:Atrial Fibrillation / Q000188:drug therapy; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D019934:International Normalized Ratio; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D054556:Venous Thromboembolism / Q000188:drug therapy; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases