title: A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II).
abstract: BACKGROUND
  Warfarin is characterized by marked variations in individual dose requirements and a narrow therapeutic window. Pharmacogenetics (PG) could improve dosing efficiency and safety, but clinical trials evidence is meager.
  
  
  RESULTS
  A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II) comprised 2 comparisons: (1) a blinded, randomized comparison of a modified 1-step (PG-1) with a 3-step algorithm (PG-2) (N=504), and (2) a clinical effectiveness comparison of PG guidance with use of either algorithm with standard dosing in a parallel control group (N=1866). A rapid method provided same-day CYP2C9 and VKORC1 genotyping. Primary outcomes were percentage of out-of-range international normalized ratios at 1 and 3 months and percentage of time in therapeutic range. Primary analysis was modified intention to treat. In the randomized comparison, PG-2 was noninferior but not superior to PG-1 for percentage of out-of-range international normalized ratios at 1 month and 3 months and for percentage of time in therapeutic range at 3 months. However, the combined PG cohort was superior to the parallel controls (percentage of out-of-range international normalized ratios 31% versus 42% at 1 month; 30% versus 42% at 3 months; percentage of time in therapeutic range 69% versus 58%, 71% versus 59%, respectively, all P<0.001). Differences persisted after adjustment for age, sex, and clinical indication. There were fewer percentage international normalized ratios ≥4 and ≤1.5 and serious adverse events at 3 months (4.5% versus 9.4% of patients, P<0.001) with PG guidance.
  
  
  CONCLUSIONS
  These findings suggest that PG dosing should be considered for broader clinical application, a proposal that is being tested further in 3 major randomized trials. The simpler 1-step PG algorithm provided equivalent results and may be preferable for clinical application.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927862.
authors.affiliation: Intermountain Medical Center, Cardiovascular Department, Murray, UT 84107-5701, USA. jeffrey.anderson@imail.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: Scott C
authors.initials: SC
authors.lastname: Woller
authors.forename: Kent M
authors.initials: KM
authors.lastname: Samuelson
authors.forename: Justin W
authors.initials: JW
authors.lastname: Mansfield
authors.forename: Michelle
authors.initials: M
authors.lastname: Robinson
authors.forename: Stephanie
authors.initials: S
authors.lastname: Barton
authors.forename: Kim
authors.initials: K
authors.lastname: Brunisholz
authors.forename: Chrissa P
authors.initials: CP
authors.lastname: Mower
authors.forename: John A
authors.initials: JA
authors.lastname: Huntinghouse
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Rollo
authors.forename: Dustin
authors.initials: D
authors.lastname: Siler
authors.forename: Tami L
authors.initials: TL
authors.lastname: Bair
authors.forename: Stacey
authors.initials: S
authors.lastname: Knight
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Muhlestein
authors.forename: John F
authors.initials: JF
authors.lastname: Carlquist
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D010597:Pharmacogenetics; D016896:Treatment Outcome; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases