Clinical trial NCT02592980: Evaluation of a Pharmacogenetic-based Warfarin Dosing Algorithm in Patients
Official title: Evaluation of a Pharmacogenetic-based Warfarin Dosing Algorithm in Patients With Low Time in Therapeutic Range - Study Design
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Atrial Fibrillation
Lead sponsor: University of Sao Paulo General Hospital
Sponsor class: OTHER
Collaborators: name: InCor Heart Institute
name: Farmoquimica S.A.
name: University of Sao Paulo
First posted: 2015-10-30
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background: 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, the investigators developed a pharmacogenetic-based warfarin dosing algorithm specifically calibrated for a Brazilian patient sample. The newly developed algorithm was shown to be more accurate for individuals from the Brazilian population than algorithms developed from international samples. 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/Design: The investigators will recruit 300 patients with TTR\<50% based on the last three INR values. At the first consultation, patients will be randomized into two groups: TA (Traditional Anticoagulation) group and PA (Pharmacogenetic Anticoagulation) group. 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. The main outcomes will be 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. Discussion: With a sample size of 150 patients for each arm separately, the study will have a power of 93% to observe a difference of 10% between TTR means of the TA and PA groups. 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.

Detailed description: Investigators will recruit 300 patients with low TTR (\<50%) from the Heart Institute- Clinical Hospital- University of São Paulo Medical School (InCor- HCFMUSP). The patients will be randomized into two groups: Traditional Anticoagulation (TA) group and Pharmacogenetic Anticoagulation (PA) group. The study protocol was approved by the Ethics Committee for Medical Research on Human Beings of the Clinical Hospital of the University of São Paulo Medical School (SDC 4033/14/013). Signed informed consent will be obtained from all participants.

Only patients with atrial fibrillation, above 18 years, and with TTR \<50% based on the last three values of INR will be included in this study. Patients will not be included if they have reached a stable dose of warfarin, liver dysfunction, alcoholism, use of another anticoagulant, use of chemotherapy, or if they do not meet the inclusion criteria.

Eligibility criteria: Inclusion Criteria:

* Only patients with atrial fibrillation, above 18 years, and with TTR \<50% based on the last three values of INR will be included in this study.

Exclusion Criteria:

* Patients will not be included if they have reached a stable dose of warfarin, liver dysfunction, alcoholism, use of another anticoagulant, use of chemotherapy, or if they do not meet the inclusion criteria

Primary outcomes:
measure: time to achieve the therapeutic target
timeFrame: 12 weeks
Secondary outcomes:
measure: TTR (time in the therapeutic range)
timeFrame: 4 weeks and 12 weeks
Other outcomes:
Locations:
city: Sao Paulo
country: Brazil
facility: Heart Institute
Study officials:
affiliation: Laboratório de Genética e Cardiologia Molecular - Instituto do Coração
name: Alexandre Pereira, M.Sc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Santos PC, Marcatto LR, Duarte NE, Gadi Soares RA, Cassaro Strunz CM, Scanavacca M, Krieger JE, Pereira AC. Development of a pharmacogenetic-based warfarin dosing algorithm and its performance in Brazilian patients: highlighting the importance of population-specific calibration. Pharmacogenomics. 2015 Jul;16(8):865-76. doi: 10.2217/pgs.15.48. Epub 2015 Jun 8.
citation: Marcatto LR, Sacilotto L, Bueno CT, Facin M, Strunz CM, Darrieux FC, Scanavacca MI, Krieger JE, Pereira AC, Santos PC. Evaluation of a pharmacogenetic-based warfarin dosing algorithm in patients with low time in therapeutic range - study protocol for a randomized controlled trial. BMC Cardiovasc Disord. 2016 Nov 17;16(1):224. doi: 10.1186/s12872-016-0405-1.