Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing: CoumaGen-II
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
- Received September 29, 2011.
- Accepted February 17, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited