Genotype-guided therapy improves initial acenocoumarol dosing

Abstract

A few trials so far have evaluated the effectiveness of algorithms designed to calculate doses in oral anticoagulant therapy, with negative or contradictory results. We compared a genotype-guided algorithm vs physician management for the initiation of acenocoumarol. In a two-arm, prospective, randomised study with patients with atrial fibrillation who started therapy, the first dose was administered to all patients according to the physician's criteria. At 72 hours, the corresponding dose was calculated based on INR in the standard care group (SC, N=92), whereas genetic data (VKORC1, CYP2C9 and CYP4F2) were also considered for the genotype-guided dosing (pharmacogenetic) group (PGx, N=87) by using an algorithm previously validated in 2,683 patients. The primary outcomes were: patients with steady dose, the time needed to reach the same and the percentage of therapeutic INRs. After 90 days, 25% of the SC and 39% of the PGx patients reached the steady dose (p=0.038). Kaplan-Meier analysis showed that PGx group needed fewer days to reach therapeutic INR (p=0.033). Additionally, PGx had a higher percentage of therapeutic INRs than SC patients (50% and 45%, respectively) (p=0.046). After six months the proportion of steadily anticoagulated patients remained significantly higher in PGx (p=0.010). In conclusion, genotype-guided dosing was associated with a higher percentage of patients with steady dose than routine practice when starting oral anticoagulation with acenocoumarol.

Dosing algorithms for vitamin K antagonists across VKORC1 and CYP2C9 genotypes

“…A recent randomized controlled trial of genotype‐guided dosing of acenocoumarol used a PG dosing algorithm developed in a Spanish population that included the VKORC1 , CYP2C9 and CYP4F2 genotypes . In this trial, the PG approach was superior to standard care in terms of the number of patients with a stable dose and the mean percentage of therapeutic INRs after 90 days of follow‐up . Although there are certainly differences in study design between this trial and EU‐PACT, it is possible that including extra genetic variants might affect the precision of dose prediction and impact on the outcome.…”

“…Taken together, VKORC1 ‐1639 G>A (rs9923231), CYP2C9 *2 (rs1799853) and CYP2C9 *3 (rs1057910) polymorphisms explain up to 30–40% of dose variability, and have been associated with anticoagulation effects of coumarins in populations of European descent . The utility of pharmacogenetic‐guided (PG) coumarin prescribing during therapy initiation has recently been investigated in prospective randomized trials . Two warfarin trials (the European Pharmacogenetics of Anticoagulant Therapy [EU‐PACT] warfarin arm, and the Clarification of Optimal Anticoagulation through Genetics [COAG] trial) produced divergent results .…”

Effect of CYP4F2,VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single‐Patient Data Meta‐Analysis in More Than 15,000 Individuals

“…In another trial that compared a genotype‐guided algorithm vs. physician management for the initiation of acenocoumarol, a higher proportion of patients in the genetic group reached and maintained a steady dose than patients randomized to routine practice when starting oral anticoagulation …”

Acenocoumarol Pharmacogenetic Dosing Algorithm versus Usual Care in Patients with Venous Thromboembolism: A Randomised Clinical Trial

“…Clinical trials to prove the utility of the pharmacogenetics in this setting were conducted after the algorithms were developed, with several trials on warfarin, comparing genotype-guided dosing versus conventional dosing and versus a clinical algorithm; however, the results have been inconsistent [15][16][17][18][19][20][21][22][23]. A number of meta-analyses have been published showing that genotype-guided dosing improves the percentage of time within the therapeutic INR range [24][25][26], although the usefulness of the pharmacogenetics in reducing bleeding complications is a subject of debate [24,[26][27][28].…”