title: Evaluation of a pharmacogenetic-based warfarin dosing algorithm in patients with low time in therapeutic range - study protocol for a randomized controlled trial.
abstract: Time in therapeutic range (TTR) is a measurement of quality of warfarin therapy and lower TTR values (<50%) are associated with greater risk of thromboembolic and bleeding events. Recently, we developed a pharmacogenetic-based warfarin dosing algorithm specifically calibrated for a Brazilian patient sample. The aims of this study are: to evaluate the impact of a genetic-based algorithm, compared to traditional anticoagulation, in the time to achieve the therapeutic target and in TTR percentage; and to assess the cost-effectiveness of genotype-guided warfarin dosing in a specific cohort of patients with low TTR (<50%) from a tertiary cardiovascular hospital.
  
  
  
  This study is a randomized controlled trial in patients (n = 300) with atrial fibrillation with TTR < 50%, based on the last three INR values. At the first consultation, patients will be randomized into two groups: TA group (traditional anticoagulation) and PA group (pharmacogenetic anticoagulation). For the first group, the physician will adjust the dose according to current INR value and, for the second group, a pharmacogenetic algorithm will be used. At the second, third, fourth and fifth consultations (with an interval of 7 days each) INR will be measured and, if necessary, the dose will be adjusted based on guidelines. Afterwards, patients who are INR stable will begin measuring their INR in 30 day intervals; if the patient's INR is not stable, the patient will return in 7 days for a new measurement of the INR. Outcomes measures will include the time to achieve the therapeutic target and the percentage of TTR at 4 and 12 weeks. In addition, as a secondary end-point, pharmacoeconomic analysis will be carried out. Ethical approval was granted by the Ethics Committee for Medical Research on Human Beings of the Clinical Hospital of the University of São Paulo Medical School.
  
  
  
  This randomized study will include patients with low TTR and it will evaluate whether a population-specific genetic algorithm might be more effective than traditional anticoagulation for a selected group of poorly anticoagulated patients.
  
  
  
  ClinicalTrials.gov, NCT02592980 . Registered on 29 October 2015.
authors.affiliation: Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, São Paulo, SP, CEP 05403-000, Brazil.
authors.forename: Leiliane Rodrigues
authors.initials: LR
authors.lastname: Marcatto
authors.affiliation: Arrhythmia Unit, Heart Institute (InCor), University of São Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, São Paulo, SP, CEP 05403-000, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Sacilotto
authors.affiliation: Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, São Paulo, SP, CEP 05403-000, Brazil.
authors.forename: Carolina Tosin
authors.initials: CT
authors.lastname: Bueno
authors.affiliation: Arrhythmia Unit, Heart Institute (InCor), University of São Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, São Paulo, SP, CEP 05403-000, Brazil.
authors.forename: Mirella
authors.initials: M
authors.lastname: Facin
authors.affiliation: Clinical Laboratory, Heart Institute (InCor), University of São Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, São Paulo, SP, CEP 05403-000, Brazil.
authors.forename: Celia Maria Cassaro
authors.initials: CM
authors.lastname: Strunz
authors.affiliation: Arrhythmia Unit, Heart Institute (InCor), University of São Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, São Paulo, SP, CEP 05403-000, Brazil.
authors.forename: Francisco Carlos Costa
authors.initials: FC
authors.lastname: Darrieux
authors.affiliation: Arrhythmia Unit, Heart Institute (InCor), University of São Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, São Paulo, SP, CEP 05403-000, Brazil.
authors.forename: Maurício Ibrahim
authors.initials: MI
authors.lastname: Scanavacca
authors.affiliation: Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, São Paulo, SP, CEP 05403-000, Brazil.
authors.forename: Jose Eduardo
authors.initials: JE
authors.lastname: Krieger
authors.affiliation: Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, São Paulo, SP, CEP 05403-000, Brazil. alexandre.pereira@incor.usp.br.
authors.forename: Alexandre Costa
authors.initials: AC
authors.lastname: Pereira
authors.affiliation: Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, São Paulo, SP, CEP 05403-000, Brazil. pacaleb@usp.br.
authors.forename: Paulo Caleb Junior Lima
authors.initials: PC
authors.lastname: Santos
mesh_terms: D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D001281:Atrial Fibrillation / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D001777:Blood Coagulation / Q000187:drug effects*; D001938:Brazil; D002985:Clinical Protocols; D054796:Drug Dosage Calculations; D016903:Drug Monitoring / Q000379:methods*; D006801:Humans; D019934:International Normalized Ratio; D010597:Pharmacogenetics; D000071185:Pharmacogenomic Testing; D000071184:Pharmacogenomic Variants; D011237:Predictive Value of Tests; D012107:Research Design; D062606:Tertiary Care Centers; D013997:Time Factors; D016896:Treatment Outcome; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000925:Anticoagulants; D014859:Warfarin
keywords: Algorithm; Pharmacoeconomy; Pharmacogenetic; Polymorphisms; Warfarin