A Randomized Trial of Genotype-Guided Dosing of Acenocoumarol and Phenprocoumon
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?
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.
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).
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.
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