Abstract
Genotype-guided warfarin dosing have been proposed to improve patient’s management. This study is aimed to determine whether a CYP2C9- VKORC1- CYP4F2-based pharmacogenetic algorithm is superior to a standard, clinically adopted, pharmacodynamic method. Two-hundred naïve patients with non-valvular atrial fibrillation were randomized to trial arms and 180 completed the study. No significant differences were found in the number of out-of-range INRs (INR<2.0 or >3.0) (p = 0.79) and in the mean percentage of time spent in the therapeutic range (TTR) after 19 days in the pharmacogenetic (51.9%) and in the control arm (53.2%, p = 0.71). The percentage of time spent at INR>4.0 was significantly lower in the pharmacogenetic (0.7%) than in the control arm (1.8%) (p = 0.02). Genotype-guided warfarin dosing is not superior in overall anticoagulation control when compared to accurate clinical standard of care.Trial RegistrationClinicalTrials.gov NCT01178034
Highlights
Despite the introduction of new oral anticoagulants with a more predictable dose response and no need for laboratory monitoring, warfarin remains the most commonly prescribed oral anticoagulant worldwide
Eleven and nine patients were excluded from the study after randomization, the final cohort consisted of 88 and 92 in the pharmacogenetic and control arm, respectively (Fig 1)
Considering only patients potentially at higher risk of over-anticoagulation i.e those requiring low warfarin maintenance doses, the distribution of international normalized ratio (INR) above 4.0, over the first 19 days of treatment, was not significantly different between arms (Bonferroni adjusted p = 0.16) the number of patients with at least one INR>4.0 was lower in the pharmacogenetic (2/26) (7.7%; 95% confidence intervals (CIs) 1.0–25.1) than in the control arm (7/28) (25.0%; 95% CI 10.7–44.9)
Summary
Despite the introduction of new oral anticoagulants with a more predictable dose response and no need for laboratory monitoring, warfarin remains the most commonly prescribed oral anticoagulant worldwide. The Achilles’ heel of warfarin use is, the drug’s wide interindividual variability in dose requirements. This makes it difficult to identify optimal loading/ maintenance doses and leads to hemorrhagic events during the initial treatment period [1]. Several methods have been proposed to safely initiate warfarin, and researchers’ efforts were intensified when specific gene polymorphisms, affecting warfarin pharmacokinetics or pharmacodynamics, were identified [2,3,4,5].
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