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

Thromboembolic events are associated with high mortality and morbidity indexes. In this context, warfarin is the most widely prescribed oral anticoagulant agent for preventing and treating these events. This medication has a narrow therapeutic range and, consequently, patients usually have difficulty in achieving and maintaining stable target therapeutics. Some studies on the literature about oral anticoagulant management showed that pharmacists could improve the efficiency of anticoagulant therapy. However, the majority of these studies included general patients retrospectively. The aim of this study was to prospectively evaluate a pharmacist’s warfarin management in patients with poor quality of anticoagulation therapy (Time in the Therapeutic Range- TTR < 50%). We included 268 patients with atrial fibrillation (AF) and without stable dose of warfarin (TTR < 50%, based on the last three values of International Normalized Ratio-INR). We followed them up for 12 weeks, INR values were evaluated and, when necessary, the dose adjustments were performed. During the first four visits, patient’s INR was measured every 7 days. Then, if INR was within the target therapeutic range (INR: 2–3), the patient was asked to return in 30 days. However, if INR was out the therapeutic target, the patient was asked to return in 7 days. Adherence evaluation was measured through questionnaires and by counting the pills taken. Comparison between basal TTR (which was calculated based on the three last INR values before prospective phase) and TTR of 4 weeks (calculated by considering the INR tests from visits 0 to 4, in the prospective phase of the study) and basal TTR and TTR of 12 weeks (calculated based on the INR tests from visits 0 to 12, in the prospective phase of the study) revealed significant statistical differences (0.144 ± 0.010 vs. 0.382 ± 0.016; and 0.144 ± 0.010 vs. 0.543 ± 0.014, p < 0.001, respectively). We also observed that the mean TTR of 1 year before (retrospective phase) was lower than TTR value after 12 weeks of pharmacist-driven treatment (prospective phase) (0.320 ± 0.015; 0.540 ± 0.015, p < 0.001). In conclusion, pharmaceutical care was able to improve TTR values in patients with AF and poor quality of anticoagulation with warfarin

Evaluation of the impact of pharmaceutical care on the quality of warfarin therapy in patients without stable dose

Eventos tromboembólicos estão associados com altas taxas de mortalidade e morbidade. Neste contexto, a varfarina é o anticoagulante oral mais prescrito para prevenir e tratar esses eventos. Este fármaco possui uma faixa terapêutica estreita e, consequentemente, é difícil atingir e manter o intervalo terapêutico. Alguns estudos mostram que o cuidado farmacêutico pode melhorar a eficiência da terapia com varfarina. Porém, não há estudos na literatura que tenham avaliado a implementação do cuidado farmacêutico em pacientes com tempo fora da faixa terapêutica (TTR < 50%) em longo prazo. Assim, os objetivos deste estudo foram avaliar: o impacto do cuidado farmacêutico em pacientes com fibrilação atrial (FA) em uso de varfarina e com baixo TTR ( < 50%); a qualidade da anticoagulação com varfarina em longo prazo, após a finalização do cuidado farmacêutico; e, o perfil de aderência à terapia com varfarina na qualidade da anticoagulação durante as 12 semanas do cuidado farmacêutico. Foram avaliados cerca de 2.600 pacientes, sendo selecionados 268 pacientes com FA e com TTR < 50%, baseado nos últimos 3 valores de razão normalizada internacional (RNI). Esses pacientes foram acompanhados por 12 semanas, recebendo o cuidado farmacêutico durante este período. No processo do cuidado farmacêutico, o farmacêutico avaliou a aderência, os eventos adversos, a interação medicamentosa e a interação alimentar e orientou os pacientes sobre sua farmacoterapia. Além disso, os valores de RNI foram avaliados e os ajustes de dose foram realizados quando necessários. Além das 12 semanas de acompanhamento, foi avaliado o TTR de cada paciente 1 ano antes do acompanhamento farmacoterapêutico e o TTR 1 ano após a finalização do cuidado farmacêutico. As comparações entre o TTR basal (que foi calculado com base nos últimos 3 valores de RNI antes da fase de acompanhamento) e o TTR de 4 semanas (que foi calculado com as RNI entre as visitas 0 e 4) e entre o TTR basal e o TTR de 12 semanas (calculado com as RNI entre as visitas 0 e 12) revelaram diferenças estatísticas (média ± erro padrão - TTR 12 semanas: 0,541 ± 0,015 vs TTR basal: 0,134 ± 0,010; p < 0,001; TTR 4 semanas: 0,383 ± 0,016 vs TTR basal: 0,134 ± 0,010; p < 0,001). Também foi observado que a média do TTR 1 ano antes de entrar no protocolo foi menor que o TTR 1 ano após a finalização do protocolo (TTR 1 ano antes: 0,313 ± 0.015 vs TTR 1 ano após: 0,565 ± 0.015; p < 0,001). Ainda, quando foi analisado o TTR em categorias, foi visto que 1 ano antes do cuidado farmacêutico, 76% (n=199) dos pacientes apresentavam TTR < 50% e 24% (n=63) dos pacientes apresentavam TTR 50%. Após 1 ano de finalização do cuidado ao paciente, somente 32% (n=83) dos pacientes apresentaram TTR < 50%, enquanto que 68% (n=179) apresentaram TTR50%. Como conclusões, a implementação do cuidado farmacêutico para pacientes com FA e com baixo TTR foi capaz de aumentar os valores de TTR e, ainda, foi capaz de manter a qualidade adquirida durante o cuidado farmacêutico 1 ano após a finalização do acompanhamento pelo profissional. Além disso, os pacientes que aderiram ao tratamento, durante o cuidado farmacêutico, tiveram melhor qualidade no tratamento do que aqueles que não aderiram à varfarina.Thromboembolic events are associated with high mortality and morbidity indexes. In this context, warfarin is the most widely prescribed oral anticoagulant agent to prevent and treat these events. This drug has a narrow therapeutic range and, consequently, it is difficult to achieve and maintain stable target therapeutics. Some studies in the literature showed that pharmaceutical care could improve the efficiency of anticoagulant therapy. However, there are no studies in the literature that evaluated the implementation of pharmaceutical care in patients with time out the therapeutic range (TTR<50%) in the long term. This way, the objectives of this study were to evaluate: the impact of pharmaceutical care on patients with atrial fibrillation (AF) using warfarin with low TTR (<50%); the quality of anticoagulation with warfarin in the long term after the finalization of the pharmaceutical care; and, the adherence profile to warfarin therapy on the quality of anticoagulation during the 12 weeks of pharmaceutical care. Approximately 2600 patients were evaluated and 268 patients with AF and with TTR<50%, based on the last 3 international normalized ratio (INR) values were included. These patients were followed up for 12 weeks, receiving pharmaceutical care during this period. In this caring process, the pharmacist evaluated: adherence; adverse events; instructed patients about the pharmacotherapy; evaluated drug and food interaction. In addition, INR were assessed and doses adjustments were performed when necessary. Furthermore, it was evaluated for each patient the TTR 1 year before the follow up and also the TTR 1 year after the end of the follow up with the pharmacist. The comparisons between basal TTR (which was calculated based on the three last INR values before the follow up stage) and TTR of 4 weeks (calculated by considering the INR tests from visits 0 to 4); and basal TTR and TTR of 12 weeks (calculated based on the INR tests from visits 0 to 12) revealed significant statistical differences (mean ± standard error- TTR of 12 weeks: 0.541 ± 0.015 vs TTR basal: 0.134 ± 0.010; p < 0.001; TTR of 4 weeks: 0.383 ± 0.016 vs basal TTR: 0.134 ± 0.010; p < 0.001). We also observed that the mean TTR value 1 year before pharmaceutical care was lower than TTR value after 1 year after the end of the protocol (TTR 1 year before:0.313 ± 0.015 vs TTR 1 year after: 0.565 ± 0.015; p < 0.001). Despite that, when TTR was analyzed in categories, it was noticed that 1 year before pharmaceutical care, 76% (n=199) of the patients showed TTR < 50% and 24% (n=63) of the patients had TTR50%. After 1 year of the end of the follow up with the pharmacist, 32% (n=83) of the patients showed TTR < 50, while 68% (n=179) had TTR50%. Concluding, the implementation of pharmaceutical care for patients with AF and with low TTR was able to increase TTR values and maintain the quality acquired during pharmaceutical care 1 year after the end of pharmaceutical follow up. In addition, the patients who adhered to the treatment with warfarin during pharmaceutical care, had a better quality of treatment than those who did not adhere to the therapy with warfarin

Pharmacogenetic evaluation for CYP2C9 and VKORC1 genes in patients that use warfarin and in the general Brazilian population

A varfarina é o anticoagulante oral mais prescrito no mundo todo. Algoritmos farmacogenéticos têm sido desenvolvidos para estimar a dose de varfarina. Os principais objetivos deste estudo foram desenvolver um algoritmo farmacogenético estimador de dose de varfarina e comparar o algoritmo desenvolvido neste trabalho com algoritmos disponíveis na literatura. Para atingir os objetivos foram incluídos dois grupos de pacientes tratados com varfarina (primeira coorte, n = 832; e segunda coorte, n = 133). Foram realizadas as genotipagens dos polimorfismos CYP2C9*2, CYP2C9*3 e VKORC1 (c.G1639A). A derivação do algoritmo foi realizada utilizando os dados dos pacientes da primeira coorte com dose estável (n=368) e foi replicado utilizando os dados dos pacientes provenientes da segunda coorte (n=133). Como resultado o algoritmo desenvolvido neste trabalho alcançou um coeficiente de determinação de 40%, incluindo as variáveis: idade, sexo, peso, altura, raça autodeclarada, uso de amiodarona, uso de indutores enzimáticos, os genótipos na VKORC1 (c.G1639A) e os fenótipos de acordo com polimorfismos CYP2C9. Os dados sugerem que o nosso algoritmo desenvolvido é mais acurado do que o algoritmo IWPC (The International Warfarin Pharmacogenetics Consortium) quando a aplicação é focada em pacientes brasileiros. Os algoritmos farmacogenéticos estimadores de dose de varfarina desenvolvidos para uma população específica podem ser mais efetivos para a terapia com varfarina em comparação com o uso de algoritmos estimadores de dose atualmente disponíveisWarfarin is the most prescribed oral anticoagulant in the world. Pharmacogenetic algorithms have been developed to estimate the dose of warfarin. The main aims of the present study were to develop a pharmacogenetic-based warfarin dosing algorithm and compare algorithm developed in this study with others algorithms available in the literature. We included two patient cohorts treated with warfarin (first cohort, n = 832; and second cohort, n = 133). Polymorphisms were genotyped in the CYP2C9 * 2, CYP2C9 * 3 and VKORC1 (c.G1639A). The derivation of the algorithm was performed using the data from the patients in the first cohort with a stable dose (n = 368) and was replicated using data from patients from the second cohort (n = 133). Our algorithm achieved a determination of coefficient of 40%, including variables: age, sex, weight, height, self-declared race, use of amiodarone, use of enzymatic inducers, genotypes in VKORC1 (c.G1639A) and phenotypes according to CYP2C9 polymorphisms. Our data suggest that the developed algorithm is more accurate than the IWPC algorithm when the application is focused on patients from the Brazilian population. Pharmacogenetics- based warfarin dosing algorithms developed for a specific population may lead to improved performance compared use dosing algorithms currently availabl

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

Abstract 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, 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/design 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. Discussion 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. Trial registration ClinicalTrials.gov, NCT02592980 . Registered on 29 October 2015

Multi-site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos

We conducted a multi-site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States (n = 411) and Brazil (n = 663) were genotyped forVKORC1c.-1639G> A, commonCYP2C9variants,CYP4F2*3, andNQO1*2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort,VKORC1andCYP2C9variants were associated with lower warfarin dose (beta = -0.29,P < 2.0 x 10(-16); beta = -0.21,P = 4.7 x 10(-7), respectively) whereasCYP4F2andNQO1variants were associated with higher dose (beta = 0.10,P = 2 x 10(-4); beta = 0.10,P = 0.01, respectively). Associations withVKORC1(beta = -0.14,P = 2.0 x 10(-16)),CYP2C9(beta = -0.07,P = 5.6 x 10(-10)), andCYP4F2(beta = 0.03,P = 3 x 10(-3)), but notNQO1*2(beta = 0.01,P = 0.30), were replicated in the Brazilians, explaining 43-46% of warfarin dose variability among the cohorts from the U.S. and Brazil, respectively. We identified genetic associations with warfarin dose requirements in the largest cohort of ancestrally diverse, warfarin-treated Latinos from the United States and Brazil to date. We confirmed the association of variants inVKORC1,CYP2C9, andCYP4F2with warfarin dose in Latinos from the United States and Brazil.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Multi‐site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos

We conducted a multi-site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States (n = 411) and Brazil (n = 663) were genotyped forVKORC1c.-1639G> A, commonCYP2C9variants,CYP4F2*3, andNQO1*2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort,VKORC1andCYP2C9variants were associated with lower warfarin dose (beta = -0.29,P < 2.0 x 10(-16); beta = -0.21,P = 4.7 x 10(-7), respectively) whereasCYP4F2andNQO1variants were associated with higher dose (beta = 0.10,P = 2 x 10(-4); beta = 0.10,P = 0.01, respectively). Associations withVKORC1(beta = -0.14,P = 2.0 x 10(-16)),CYP2C9(beta = -0.07,P = 5.6 x 10(-10)), andCYP4F2(beta = 0.03,P = 3 x 10(-3)), but notNQO1*2(beta = 0.01,P = 0.30), were replicated in the Brazilians, explaining 43-46% of warfarin dose variability among the cohorts from the U.S. and Brazil, respectively. We identified genetic associations with warfarin dose requirements in the largest cohort of ancestrally diverse, warfarin-treated Latinos from the United States and Brazil to date. We confirmed the association of variants inVKORC1,CYP2C9, andCYP4F2with warfarin dose in Latinos from the United States and Brazil.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]