Log in to MyACC
A Randomized Trial of Genotype-Guided Dosing of Acenocoumarol and Phenprocoumon
Study Questions:
What are the effectiveness and safety of a genotype-guided dosing algorithm of acenocoumarol and phenprocoumon therapy, compared to a dosing algorithm that includes only clinical variables?
Methods:
The EU-PACT (European Pharmacogenetics of Anticoagulant Therapy) trial authors conducted two single-blind, randomized trials in patients with atrial fibrillation or venous thromboembolism newly initiated on therapy with acenocoumarol and phenprocoumon. During the first week of treatment, patients randomized to the genotype-guided group were treated according to a dosing algorithm that included VKORC1 and CYP2C9 genotype information, and those in the control group were treated according to a dosing algorithm based solely on clinical variables. After the first 5-7 days, patients were treated on the basis of the international normalized ratio (INR) and local practice. Intended follow-up was 12 weeks. The primary outcome was the percentage of time in the therapeutic INR range (2.0-3.0). Secondary outcomes included the percentage of time with an INR of ≥4.0 or with an INR of <2.0. The study was not powered to assess bleeding and thrombotic complications.
Results:
The sample in the intention-to-treat population included 484 patients. The time in the therapeutic range was 61.6% in the genotype-guided group and 60.2% in the control group receiving clinically guided dosing (p = 0.52). Although the percentage of time in the therapeutic range during the first 4 weeks after the initiation of treatment in the two groups was 52.8% and 47.5% (p = 0.02), respectively, there were no significant differences between the two groups for several secondary outcomes (including the percentage of time with an INR of ≥4.0 or an INR of <2.0).
Conclusions:
A dosing regimen for acenocoumarol or phenprocoumon based on both pharmacogenetic and clinical factors, compared to a dosing algorithm based solely on clinical variables, does not improve the percentage of time in the therapeutic INR range during 12 weeks following initiation of therapy.
Perspective:
The results from these two randomized trials of genotype-guided dosing of acenocoumarol or phenprocoumon versus clinical-based dosing suggest that pharmacogenetic testing probably has little role in the initial dosing of these vitamin K antagonists. As the CYP2C9 has greater influence on the pharmacokinetics of warfarin, dosing based on both pharmacogenetic and clinical factors may have a different impact on the time spent in the therapeutic INR range for patients taking warfarin, compared to the vitamin K antagonists included in this study.
Keywords: Venous Thromboembolism, Genotype, Single-Blind Method, Pharmacogenetics
< Back to Listings
