title: Genotype-guided therapy improves initial acenocoumarol dosing. Results from a prospective randomised study.
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.
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Cerezo-Manchado
authors.affiliation: Vanessa Roldán, Sº Hematologia y Oncologia Medica, Hospital Universitario Morales Meseguer, Avda. Marqués de los Vélez s/n, 30008 Murcia, Spain, Tel./Fax: +34 968360969, E-mail: vroldans@um.es.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Roldán
authors.forename: Javier
authors.initials: J
authors.lastname: Corral
authors.forename: Mario
authors.initials: M
authors.lastname: Rosafalco
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Antón
authors.forename: Jose
authors.initials: J
authors.lastname: Padilla
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
authors.forename: Rocio
authors.initials: R
authors.lastname: González-Conejero
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001777:Blood Coagulation / Q000187:drug effects*; D016009:Chi-Square Distribution; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D054796:Drug Dosage Calculations; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods*; D010641:Phenotype; D057285:Precision Medicine / Q000379:methods*; D011237:Predictive Value of Tests; D011446:Prospective Studies; D013030:Spain; D064417:Vitamin K Epoxide Reductases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol
keywords: Acenocoumarol; algorithm; cytochromes; human; pharmacogenetics; subunit 1 protein; vitamin K epoxide reductase complex