Evaluation of a pharmacogenetic-based warfarin dosing algorithm in patients with low time in therapeutic range – study protocol for a randomized controlled trial

Abstract

BackgroundTime 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.Methods/designThis 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.DiscussionThis 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.Trial registrationClinicalTrials.gov, NCT02592980. Registered on 29 October 2015.

Dose Não Usual De Varfarina Para Alcançar Rni Terapêutica Em Uma Criança De Quatro Meses: Fatores De Risco Não Genéticos Ainda São Um Desafio

“… 6 , 8 It is worth noting that VKORC and CYP2C9 gene polymorphism screening have been issued as an essential laboratory test before initiating warfarin. 9 , 10 While the clinical value of such exam has been associated with improved safety, 9 , 10 the cost-effectiveness 11 of universal testing of patients initiating vitamin K antagonists still is to be determined, especially in public health systems. A randomized trial 11 of routine VKORC and CYP2C9 polymorphism testing will also analyze how cost-effective is such technology in Brazil, in order to assess the priority of such pharmacogenetics information.…”

Evaluation of the Long-Term Impact on Quality After the End of Pharmacist-Driven Warfarin Therapy Management in Patients With Poor Quality of Anticoagulation Therapy

“…We excluded patients with liver and/or kidney dysfunctions (AST- aspartate aminotransferase/ALT- alanine aminotransferase >3x normal; creatinine >2.26 mg/dl or >200 µmol/L or GFR<60 mL/min/1,73m 2 ), alcoholism (≥8 drinks/week), valvular heart disease, use of another anticoagulant, chemotherapy treatment and patients who had changed their amiodarone dosage 1 week before entering the study ( Marcatto et al., 2016a ).…”

“…5Dose adjustment occurred according to the guidelines in the same way for all visits. In addition, we used the EP mobile tool for assisting in the management of the weekly dose ( Horton and Bushwick, 1999 ; Ansell et al., 2008 ; Cushman et al., 2011 ): INR values ≤1.5, increased by 20%; >1.5 to < 2.0, increased by 5%; >3.0 to 3.5, decreased by 5%; >3.5 to <5.0 decreased by 20%; >5.0 to 9.0 decreased by 20% and omitted two doses and considered use of oral vitamin K; >9.0 discontinued warfarin for 7 days and considered administering vitamin K ( Horton and Bushwick, 1999 ; Ansell et al., 2008 ; Cushman et al., 2011 ; Marcatto et al., 2016a ).…”

Pharmaceutical Care Increases Time in Therapeutic Range of Patients With Poor Quality of Anticoagulation With Warfarin

“…After visit 4, if the patient’s INR was within the target therapeutic range (INR: 2–3), the next INR measurement was assessed after 30 days. If the patient’s INR was not within the target therapeutic range, the warfarin dose adjustment was performed and the INR measurement was repeated after 7 days, until 12 weeks of follow-up were completed ( Marcatto et al, 2016a ).…”