Objectives

The COAG trial tested whether genotype-guided dosing of warfarin improves anticoagulation control during the first 4 weeks of therapy when compared to clinical-guided dosing.

Background

Warfarin is highly efficacious at preventing thromboembolism, a condition associated with substantial morbidity and mortality. Individuals taking warfarin require dosage adjustments to maintain a therapeutic international normalized ratio (INR), particularly at the beginning of therapy. Out of range INR can increase risk of thromboembolism, bleeding, and early discontinuation of a highly useful therapy. Genotype-guided dosing of warfarin may be a more effective way of dosing warfarin when compared to only using clinical information. Observational studies have identified two genes, CYP2C9 and VKORC1, that are associated with variation in warfarin maintenance doses. Prior to the COAG trial, the effectiveness of genotype-guided dosing of warfarin had been limited to small clinical trials or observational studies, with equivocal results. Therefore comparison of the two strategies was needed to determine if use of genetic information is more effective in warfarin dosing than using clinical information.

Participants

Participants were adults initiating warfarin therapy with a target international normalized ratio (INR) of 2 to 3 and an expected duration of therapy of at least 1 month. Exclusion criteria included current warfarin use, prior warfarin therapy with a known stable dose, and abnormal baseline INR (off warfarin). A total of 1015 subjects were enrolled in the study.

Design

The COAG study was a multicenter, double-blind, randomized trial that compared two approaches to guiding warfarin therapy initiation. Subjects were randomly assigned in a 1:1 ratio to a dosing strategy during the first 5 days of warfarin therapy. For each dosing strategy, a dose-initiation algorithm was used during the first 3 days of therapy, and a dose-revision algorithm was used on day 4, 5, or both. The algorithms for the genotype-guided dosing strategy included clinical variables and genotype data for CYP2C92, CYP2C93, and VKORC1. The algorithms for the clinically based dosing strategy included clinical variables only. If genotype information was not available for a patient in the genotype-guided dosing group before the administration of warfarin on any given day in the first 5 days, the clinical algorithm was used on that day.

During the first 4 weeks of therapy, patients and clinicians were unaware of the actual dose of warfarin that was administered. After the 5-day initiation period, dosage was adjusted during the first 4 weeks using standardized dose-adjustment techniques, starting with the doses predicted by the algorithms and making the same relative adjustments on the basis of the INR in the two study groups. Clinicians were informed of the relative dose change at each INR measurement but not the actual dose of warfarin. Subjects were to be followed for a total of 6 months.

The primary outcome was the percentage of time that the subject’s INR was in the therapeutic range (2 to 3) from the completion of the intervention period (day 4 or 5) through day 28 of therapy. Secondary outcomes included a composite outcome of any INR of 4 or more, major bleeding, or thromboembolism in the first 4 weeks.

Conclusions

Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy.

N Engl J Med. 2013 Dec 12; 369(24): 2283–2293.

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