A pharmacogenetic versus a clinical algorithm for warfarin dosing

Abstract

Background: The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results.

Methods: We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy.

Results: At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy.

Conclusions: Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.).

Figure 1. Distribution of Time in the Therapeutic Range

Side-by-side density plots show the distribution of the percentage of time in the therapeutic range of the international normalized ratio (INR) from the completion of the intervention period (day 4 or 5) to day 28 of therapy for the two study groups among all patients (at left), among patients stratified according to the absolute difference in the predicted initial daily dose of warfarin between the two algorithms (=1 mg [primary subgroup] vs. <1 mg) (at top right), and among patients stratified according to race (at bottom right). The horizontal lines indicate the mean percentage of time in the therapeutic range.

Figure 2. Range of INRs during the 4-Week Study

Shown are the INRs from the completion of the intervention period (day 4 or 5) to day 28 of therapy in the two study groups. Solid lines represent smoothing splines with 5 degrees of freedom. Dashed lines represent the 20th and 80th percentiles of INR values calculated over a 3-day window.