Clarification of Optimal Anticoagulation through Genetics (2013)


Initiating anticoagulation with warfarin

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Observational studies have identified two genes, CYP2C9 and VKORC1, that are associated with variation in warfarin maintenance doses. The aim of this trial was to test the hypothesis that initiating warfarin therapy at a genotype-guided maintenance dose for the first 5 days, as compared with
initiating warfarin at a clinically predicted maintenance dose, improves anticoagulation control

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Trial design

Randomized, double-blind, controlled study using two different strategies to choose the initial warfarin dose
Active treatment: During the first 5 days of anticoagulation the patients received warfarin at the maintenance dose predicted by prespecified algorithms that included both clinical variables and genotype data for CYP2C9*2, CYP2C9*3, and VKORC1 (n=514)
Control treatment: In the 5-day initiation period patients were treated with warfarin doses determined according to a dosing algorithm that included only clinical variables such age, race, body size, smoking status, and use of certain cardiovascular medications (n=501)
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. After the 5-day initiation period, the dose was adjusted during the first 4 weeks of therapy, 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. The clinicians were informed of the relative dose change at each INR measurement but not of the actual dose of warfarin. All patients were to be followed for a total of 6 months

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Primary outcome: percentage of time in therapeutic range (INR=2.0–3.0) from day 4 or 5 through day 28 of warfarin therapy in the entire study population and in the subgroup with ≥1.0 mg/day difference in warfarin dose as determined by genotype- or clinical-only dosing
Secondary outcome: composite of any INR value ≥4, major bleeding, or thromboembolism in the first 4 weeks, time to the first therapeutic INR, adverse events

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Trial participants

1015 patients ≥18 years of age with a clinical condition requiring anticoagulation with warfarin were enrolled. Genotype data were available in the genotype-guided group for 45% of the patients before the first warfarin dose, for 94% before the second warfarin dose, and for 99% before the application of the dose-revision algorithm on day 4 or 5

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Primary outcome: At 4 weeks, the mean percentage of time in the therapeutic range (PTTR) was 45.2% in the genotype-guided group and 45.4% in the clinically guided group. The between group-difference was not significant (p=0.91). No benefit of genotype-guided dosing of warfarin was observed, 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. Among African Americans, the PTTR was 35.2% for the genotype-guided group and 43.5% in the clinically guided group (p=0.01)
Secondary outcome: 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 (p=0.93)

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

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Kimmel SE, French B, Kasner SE, Johnson JA, Anderson JL, Gage BF, Rosenberg YD, Eby CS, Madigan RA, McBane RB, Abdel-Rahman SZ, Stevens SM, Yale S, Mohler ER 3rd, Fang MC, Shah V, Horenstein RB, Limdi NA, Muldowney JA 3rd, Gujral J, Delafontaine P, Desnick RJ, Ortel TL, Billett HH, Pendleton RC, Geller NL, Halperin JL, Goldhaber SZ, Caldwell MD, Califf RM, Ellenberg JH; COAG Investigators. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med 2013;369:2283-2293

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Corresponding author

Stephen E Kimmel, MD, Center for Therapeutic Effectiveness Research, 923 Blockley Hall, 423 Guardian Dr., Philadelphia, PA 19104-6021, e-mail:

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