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A Pharmacogenetic Versus a Clinical Algorithm for Warfarin Dosing
Study Questions:
What is the effect of genotype-guided dosing on anticoagulation control?
Methods:
The COAG (Clarification of Optimal Anticoagulation Through Genetics) trial investigators randomly assigned 1,015 patients to receive doses of warfarin during the first 5 days of therapy, which 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 four or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy.
Conclusions:
The authors concluded that genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy.
Perspective:
This study reported no benefit of genotype-guided dosing of warfarin with respect to the primary outcome of the percentage of time in the therapeutic INR range, either overall or among patients with a predicted dose difference between the genotype-guided algorithm and the clinically guided algorithm of at least 1 mg per day. Overall, these findings exclude a meaningful effect of genotype-guided dosing on the percentage of time in the therapeutic range during the first month of warfarin treatment. 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: Thromboembolism, Blood Coagulation, Warfarin, Genotype, Pharmacogenetics, Hemorrhage
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