A Randomized Trial of Genotype-Guided Dosing of Warfarin

Jan 03, 2014
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Authors:
Pirmohamed M, Burnside G, Eriksson N, et al., on behalf of the EU-PACT Group.
Citation:
N Engl J Med 2013;369:2294-2303.
Summary By:
Debabrata Mukherjee, MD, FACC

Study Questions:

What is the effect of genotype-guided dosing on anticoagulation control?

Methods:

The EU-PACT Warfarin investigators conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (−1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0-3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation.

Results:

A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3-10.6; p < 0.001). There were significantly fewer incidences of excessive anticoagulation (INR ≥4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (p < 0.001).

Conclusions:

The authors concluded that pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy.

Perspective:

This study reported that genotype-based dosing at the initiation of warfarin therapy increased the time in the therapeutic range by 7 percentage points, and reduced the incidence of excessive anticoagulation. The results at 12 weeks for percentage of time in the therapeutic INR range were 67.4% and 60.3%, which are significantly different albeit similar, indicating only a modest improvement. Two other major trials reported no usefulness in the initial dosing of vitamin K antagonists with genotyping, and this study shows only marginal usefulness. It appears that we may be better served by concentrating on improvements in the infrastructure for INR testing, including better communication among the laboratory, the physician, and the patient in the use of formal algorithms for dosing, without concern for genotype; in patient adherence to therapy and possibly more responsibility for dosing being assumed by the patient.

Keywords: Vitamin K, Blood Coagulation, Warfarin, Venous Thromboembolism, Atrial Fibrillation, Confidence Intervals


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