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

Study Questions:

What is the impact of pharmacogenetics (PG) on improving dosing efficiency and safety of warfarin?


The CoumaGen-II trial was comprised of two 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 = 1,866). 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 months, and time in therapeutic range (TTR). Primary analysis was modified intention to treat.


In the randomized comparison, PG-2 was noninferior, but not superior to PG-1 for %OOR INR at 1 and 3 months, and for %TTR at 3 months. However, the combined PG cohort was superior to the parallel controls (%OOR INRs 31% vs. 42% at 1 month; 30% vs. 42% at 3 months; %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 months (4.5% vs. 9.4% of patients) (p < 0.001) with PG-guidance.


The authors concluded that PG-dosing should be considered for broader clinical application.


This study suggests that pharmacogenetic dosing of warfarin was associated with substantially reduced % out-of-range INRs and increased time in therapeutic range. Furthermore, PG-guidance was associated with fewer serious adverse events. More complex PG dosing did not add significantly to dosing-efficiency, suggesting that the simpler PG-1 algorithm may be preferable for general clinical application. These findings are not sufficiently definitive to establish PG-dosing as a general therapeutic mandate, but need further testing in prospective randomized trials with hard clinical endpoints.

Clinical Topics: Anticoagulation Management

Keywords: Antipsychotic Agents, Cardiology, Warfarin, Clozapine, Mixed Function Oxygenases

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