Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing: CoumaGen-II.

Anderson JL, Horne BD, Stevens SM, Woller SC, Samuelson KM, Mansfield JW, Robinson M, Barton S, Brunisholz K, Mower CP, Huntinghouse JA, Rollo JS, Siler D, Bair TL, Knight S, Muhlestein JB, Carlquist JF.

Source

1 Intermountain Healthcare & University of Utah School of Medicine, Salt Lake City, UT;

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.

METHODS AND RESULTS:

CoumaGen-II comprised 2 comparisons: 1) a blinded, randomized comparison of a modified 1-stage (PG-1) with a 3-stage algorithm (PG-2) (N=504), and 2) a clinical effectiveness comparison of PG-guidance using 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 % out-of-range (OOR) international normalized ratios (INRs) at 1 and 3 mo and time in therapeutic range (TTR). Primary analysis was modified intention to treat. In the randomized comparison, PG-2 was non-inferior but not superior to PG-1 for %OOR INR at 1 mo and 3 mo and for %TTR at 3 mo. However, the combined PG cohort was superior to the parallel controls (%OOR INRs 31% vs. 42% at 1 mo; 30% vs. 42% at 3 mo; %TTR 69% vs. 58%, 71% vs. 59%, respectively, all p <0.001). Differences persisted after adjustment for age, sex, and clinical indication. There were fewer %INRs ≥4 and ≤1.5 and serious adverse events at 3 mo (4.5% vs. 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-stage PG algorithm provided equivalent results and may be preferable for clinical application. CLINICAL TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov; NCT00927862.