Genotype testing for warfarin dosing may offer limited or no benefit

Genotyping for warfarin therapy has limited, if any, benefit, according to 3 recent studies and an editorial.

The research was presented at the American Heart Association's Scientific Sessions and appeared online Nov. 19 at the New England Journal of Medicine. In the first study, researchers randomized 1,015 U.S. inpatients and outpatients with a target international normalized ratio (INR) of 2.0 to 3.0 to receive doses of warfarin during the first 5 days of therapy that were determined either by a dosing algorithm including clinical variables and genotype data or only clinical variables. The dose of warfarin was double-blinded during the first 4 weeks of therapy.

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, −0.2; 95% CI, −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 2 algorithms of 1 mg per day or more. Researchers concluded that there was no benefit of genotype-guided dosing of warfarin on time in the therapeutic INR range during the first month of treatment. The authors wrote, “Our results emphasize the importance of performing randomized trials for pharmacogenetics, particularly for complex regimens such as warfarin.”

A second multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism found 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. The researchers used a pharmacogenetic loading-dose algorithm that took into account the effect of CYP2C9*2, CYP2C9*3, and VKORC1 (−1639G→A) on warfarin.

A total of 455 warfarin-naive patients who had either atrial fibrillation or venous thromboembolism and required warfarin with a target INR of 2.0 to 3.0 were recruited from 3 U.K. centers and 2 in Sweden. In the study, 227 patients were randomized to the genotype-guided group and 228 to the control group. Patients in the genotype-guided group received warfarin doses per the pharmacogenetic algorithms for the first 5 days. Patients in the control group received a 3-day loading-dose regimen.

The mean percentage of time in the therapeutic range was 67.4% in the pharmacogenetic group, compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% CI, 3.3 to 10.6 percentage points; P<0.001). The pharmacogenetic group experienced significantly fewer incidences of excessive anticoagulation (INR ≥4.0) than the control 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).

The differences in the mean INR between the 2 groups were greatest soon after starting anticoagulation and waned during the 3-month follow-up period. The researchers wrote, “Our algorithmic strategy reduced the likelihood of excessive anticoagulation (INR ≥4.0) in the early stages of anticoagulation, while reducing the time to achieve a therapeutic INR, suggesting that genotype-guided dosing may not only prove to be safer but may also reduce the time required for stabilization when adopting a loading-dose strategy.”

The researchers noted that the study looked at time in the therapeutic range, rather than the clinical outcomes of bleeding and thrombosis. It was underpowered to detect a reduction in bleeding events, and it did not use a double-blind design. The majority of patients were of European ethnic background, and algorithms specific to ethnic groups will need to be developed. They added the caveat that it is not yet clear whether these results would translate to better clinical outcomes.

A third study addressed genotype-guided therapy with acenocoumarol or phenprocoumon, which are not approved for use in the United States. The percentage of time in the therapeutic INR range was 61.6% for patients receiving genotype-guided dosing and 60.2% for those receiving clinically guided dosing (P=0.52). The percentage of time in the therapeutic range during the first 4 weeks after starting treatment was 52.8% and 47.5% (P=0.02), respectively. There were no significant differences between the 2 groups for several secondary outcomes, nor for bleeding or thromboembolic events.

An editorial concluded that the 3 trials showed that pharmacogenetic testing either isn't useful when prescribing vitamin K agonists or is, at best, marginally so, given the cost and effort required.

The editorialist wrote, “Perhaps we should concentrate on improvements in the infrastructure for INR testing, including better communication among the laboratory, the physician, and the patient (e.g., through social media); 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; and in increased diligence by medical and paramedical personnel in testing, monitoring, and dosing on the basis of the INR, given the high percentage of medical mismanagement associated with these anticoagulant agents.”