A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II)

作者：Anderson Jeffrey L^*; Horne Benjamin D; Stevens Scott M; Woller Scott C; Samuelson Kent M; Mansfield Justin W; Robinson Michelle; Barton Stephanie; Brunisholz Kim; Mower Chrissa P; Huntinghouse John A; Rollo Jeffrey S; Siler Dustin; Bair Tami L; Knight Stacey; Muhlestein Joseph B; Carlquist John F

来源：Circulation, 2012, 125(16): 1997-+.

DOI：10.1161/CIRCULATIONAHA.111.070920

• anticoagulants
• clinical trial
• genetics
• pharmacogenetics
• warfarin

Background-Warfarin is characterized by marked variations in individual dose requirements and a narrow therapeutic Pharmacogenetics (PG) could improve dosing efficiency and safety, but clinical trials evidence is meager.
Methods and 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. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927862. (Circulation. 2012; 125: 1997-2005.)

• 出版日期2012-4-24