RESUMEN

BACKGROUND: Prevalence of bioprosthetic valve degeneration (BVD) is rising as the use of bioprosthetic aortic valves increases. Detecting early signs of BVD remains a challenge, with conventional imaging methods often failing to identify early deterioration stages. 18F-fuoride positron emission tomography (PET-CT) is an emerging technique that offers promising prospects to detect subclinical BVD. This study aimed to compare early PET parameters of fluoride uptake with echocardiographic hemodynamic parameters and compare outcomes according to anticoagulation in patients who received bioprosthetic valves. METHODS: This is a sub-study of the ANTIPRO clinical trial, which involved patients undergoing surgical aortic valve replacement (SAVR) with a porcine bioprosthesis and randomized them into anticoagulated and non-anticoagulated groups. Hemodynamic changes were assessed by transthoracic echocardiography (TTE), while 18F-fluoride PET-CT quantified fluoride uptake and divided the patients in two groups: high-uptake and low-uptake. Mean and maximum gradients by TTE at three years were compared between the two uptake groups. Fluoride uptake was also compared between the anticoagulated and control groups. RESULTS: We found no significant differences in transprosthetic gradients between high-uptake(21.4 ± 8.6 mmHg) and low-uptake(17.3 ± 11.2 mmHg.p = 0.244) PET-defined groups in this specific timeframe. Notably, anticoagulated patients exhibited significantly risk of higher fluoride uptake(OR = 4.34;95%CI:1.04-18.21.p = 0.045). CONCLUSIONS: No association was found between fluoride uptake and hemodynamic evaluation. Anticoagulation was associated with higher fluoride uptake. These findings highlight the emerging role of PET-CT in studying bioprosthetic aortic valves and emphasize the need for extended follow-up to evaluate the impact of anticoagulation on valve degeneration.

Asunto(s)

Anticoagulantes , Válvula Aórtica , Bioprótesis , Prótesis Valvulares Cardíacas , Warfarina , Bioprótesis/efectos adversos , Humanos , Femenino , Masculino , Prótesis Valvulares Cardíacas/efectos adversos , Anticoagulantes/administración & dosificación , Anciano , Warfarina/administración & dosificación , Warfarina/farmacocinética , Warfarina/uso terapéutico , Válvula Aórtica/cirugía , Válvula Aórtica/diagnóstico por imagen , Radioisótopos de Flúor , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Persona de Mediana Edad , Estenosis de la Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estudios de Seguimiento , Falla de Prótesis , Tomografía de Emisión de Positrones/métodos

RESUMEN

Lograr un adecuado nivel de anticoagulación con antagonistas orales de la vitamina K suele ser un desafío frecuente en la práctica clínica, dado que su estrecho rango terapéutico suele verse afectado por diversas interacciones farmacológicas,alimentos y condiciones clínicas. A partir de un caso de un paciente anticoagulado que presenta una hemorragia gastro-intestinal posterior a realizar un tratamiento antibiótico, la autora de este artículo revisó la evidencia sobre el riesgo desangrado secundario a la interacción entre este tipo de anticoagulantes y antibióticos orales. Su conclusión tras realizar una búsqueda bibliográfica y seleccionar la mejor evidencia disponible, es que existe un aumento del riesgo relativo desangrado en pacientes anticoagulados que reciben antibióticos, por lo que deberían evitarse aquellos antibióticos con conocido potencial de interacción. Si ello no fuera posible, se recomienda monitorizar el estado de anticoagulación con dosaje de la razón internacional normatizada (RIN) posterior a la introducción del antibiótico. (AU)

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Achieving an adequate level of anticoagulation with oral vitamin K antagonists is often a frequent challenge in clinical practice, given that their narrow therapeutic range is often affected by various drug interactions, food, and clinical conditions. Based on a case of an anticoagulated patient who presented gastrointestinal bleeding after antibiotic treatment, the authorof this article reviewed the evidence on the risk of secondary bleeding due to the interaction between this type of anticoagulants and oral antibiotics. Their conclusion, after performing a literature search and selecting the best available evidence, is that there is an increased relative risk of bleeding in anticoagulated patients receiving antibiotics, so antibiotics with known potential for interaction should be avoided. If it weren't possible, it is recommended to monitor the anticoagulation status with International Normalized Ratio (INR) dosing after the introduction of the antibiotic. (AU)

Asunto(s)

Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Adulto Joven , Vitamina K/antagonistas & inhibidores , Warfarina/efectos adversos , Hemorragia/inducido químicamente , Acenocumarol/efectos adversos , Antibacterianos/efectos adversos , Anticoagulantes/efectos adversos , Warfarina/farmacología , Warfarina/farmacocinética , Factores de Riesgo , Medición de Riesgo , Relación Normalizada Internacional , Interacciones Farmacológicas , Acenocumarol/farmacología , Acenocumarol/farmacocinética , Antibacterianos/farmacología , Anticoagulantes/farmacología , Anticoagulantes/farmacocinética

RESUMEN

We searched PubMed entries and the Lattes database of Brazilian Pharmacogenetics Network investigators, for pharmacogenetic/genomic (PGx) studies in the Brazilian population, focusing on the drugs and genes included in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Warfarin was the most extensively studied drug in a PGx context: a genomewide association study targeting warfarin stable dose identified significant signals in VKORC1 and CYP2C9, several PGx dosing algorithms were developed based on these and other genes, and the implications of population admixture on extrapolation of dosing recommendations in the CPIC guidelines were examined. A study in renal transplanted patients disclosed association of CYP3A5*6 and CYP3A5*7 with tacrolimus dosing, which led to addition of these variants to CYP3A5*3 in the CPIC tacrolimus guideline. Studies verified predisposition of HIV-positive carriers of UGT1A1*28 to severe atazanavir-induced hyperbilirubinaemia, intolerance to 5-fluorouracyl in gastrointestinal cancer patients with deleterious DPYD variants, failure of HCV-infected carriers of IFNL3 rs12979860 to obtain a sustained viral response to PEG-IFN-α, and hypersensitivity reactions to abacavir in HIV-positive carriers of HLA-B*57:01. No prospective analyses of drug therapy outcomes or cost-effectiveness assessments of PGx-guided therapy were found. In conclusion, the limited adoption of PGx-informed drug prescription in Brazil reflects combination of recognized barriers to PGx implementation worldwide plus factors specific to the Brazilian population. The latter include rarity/absence of genetic variants on which international PGx guidelines are based (eg HLA-B*15.02 for phenytoin and carbamazepine) and the caveat of extrapolating to the admixed Brazilian population, guidelines based on categorical variables, such as continental ancestry (eg warfarin guidelines), "race" or ethnicity.

Asunto(s)

Farmacogenética , Anticoagulantes/administración & dosificación , Anticoagulantes/farmacocinética , Brasil , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Humanos , Warfarina/administración & dosificación , Warfarina/farmacocinética

RESUMEN

The products of the polymorphic ADME genes are involved in Absorption, Distribution, Metabolism, and Excretion of drugs. The pharmacogenetic data have been studied extensively due to their clinical importance in the appropriate drug prescription, but such data from the isolated populations are rather scarce. We analyzed the distribution of 95 polymorphisms in 31 core ADME genes in 20 populations worldwide and in newly genotyped samples from the Roma (Gypsy) population living in Croatia. Global distribution of ADME core gene loci differentiated three major clusters; (1) African, (2) East Asian, and (3) joint European, South Asian and South American cluster. The SLCO1B3 (rs4149117) and CYP3A4 (rs2242480) genes differentiated at the highest level the African group of populations, while NAT2 gene loci (rs1208, rs1801280, and rs1799929) and VKORC1 (rs9923231) differentiated East Asian populations. The VKORC1 rs9923231 was among the investigated loci the one with the largest global minor allele frequency (MAF) range; its MAF ranged from 0.027 in Nigeria to 0.924 in Han Chinese. The distribution of the investigated gene loci positions Roma population within the joined European and South Asian clusters, suggesting that their ADME gene pool is a combination of ancestral (Indian) and more recent (European) surrounding, as it was already implied by other genetic markers. However, when compared to the populations worldwide, the Croatian Roma have extreme MAF values in 10 out of the 95 investigated ADME core gene loci. Among loci which have extraordinary MAFs in Roma population two have strong proof of clinical importance: rs1799853 (CYP2C9) for warfarin dosage, and rs12248560 (CYP2C19) for clopidogrel dosage, efficacy and toxicity. This finding confirms the importance of taking the Roma as well as the other isolated populations`genetic profiles into account in pharmaco-therapeutic practice.

Asunto(s)

Clopidogrel/farmacocinética , Citocromo P-450 CYP2C19/genética , Variantes Farmacogenómicas , Romaní/genética , Warfarina/farmacocinética , África/etnología , Arilamina N-Acetiltransferasa/genética , Asia/etnología , Croacia/etnología , Citocromo P-450 CYP3A/genética , Frecuencia de los Genes , Genética de Población , Migración Humana , Humanos , Polimorfismo de Nucleótido Simple , Análisis de Componente Principal , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/genética , América del Sur/etnología , Vitamina K Epóxido Reductasas/genética

RESUMEN

PURPOSE: Interpatient variation of warfarin dose requirements may be explained by genetic variations and general and clinical factors. In this scenario, diverse population-calibrated dosing algorithms, which incorporate the main warfarin dosing influencers, have been widely proposed for predicting supposed warfarin maintenance dose, in order to prevent and reduce adverse events. The aim of the present study was to evaluate the impact of the inclusion of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms as additional covariates in a previously developed pharmacogenetic-based warfarin dosing algorithm calibrated for the Brazilian population. METHODS: Two independent cohorts of patients treated with warfarin (n = 832 and n = 133) were included for derivation and replication of the algorithm, respectively. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms was performed by polymerase chain reaction followed by melting curve analysis and TaqMan® assay, respectively. A multiple linear regression was performed for the warfarin stable doses as a dependent variable, considering clinical, general, and genetic data as covariates. RESULTS: The inclusion of ABCB1 and CYP4F2 polymorphisms was able to improve the algorithm's coefficient of determination (R2) by 2.6%. In addition, the partial determination coefficients of these variants revealed that they explained 3.6% of the warfarin dose variability. We also observed a marginal improvement of the linear correlation between observed and predicted doses (from 59.7 to 61.4%). CONCLUSION: Although our study indicates that the contribution of the combined ABCB1 and CYP4F2 genotypes in explaining the overall variability in warfarin dose is not very large, we demonstrated that these pharmacogenomic data are statistically significant. However, the clinical relevance and cost-effective impact of incorporating additional variants in warfarin dosing algorithms should be carefully evaluated.

Asunto(s)

Algoritmos , Anticoagulantes/administración & dosificación , Familia 4 del Citocromo P450/genética , Farmacogenética , Polimorfismo Genético/genética , Warfarina/administración & dosificación , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Anciano , Anticoagulantes/farmacocinética , Brasil , Estudios de Cohortes , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Warfarina/farmacocinética

RESUMEN

Warfarin pharmacogenomics has been an extensively studied field in the last decades as it is focused on personalized therapy to overcome the wide interpatient warfarin response variability and decrease the risk of side effects. In this expert review, besides briefly summarizing the current knowledge about warfarin pharmacogenetics, we also present an overview of recent studies that aimed to assess the efficacy, safety and economic issues related to genotype-based dosing algorithms used to guide warfarin therapy, including randomized and controlled clinical trials, meta-analyses and cost-effectiveness studies. To date, the findings still present disparities, mostly because of standard limitations. Thus, further studies should be encouraged to try to demonstrate the benefits of the application of warfarin pharmacogenomic dosing algorithms in clinical practice.

Asunto(s)

Anticoagulantes , Farmacogenética , Medicina de Precisión , Warfarina , Algoritmos , Anticoagulantes/administración & dosificación , Anticoagulantes/farmacocinética , Anticoagulantes/uso terapéutico , Biomarcadores Farmacológicos , Sistema Enzimático del Citocromo P-450/genética , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Farmacogenómica , Polimorfismo de Nucleótido Simple , Vitamina K Epóxido Reductasas/genética , Warfarina/administración & dosificación , Warfarina/farmacocinética , Warfarina/uso terapéutico

Asunto(s)

Anticoagulantes/uso terapéutico , Citocromo P-450 CYP2C9/genética , Vitamina K Epóxido Reductasas/genética , Warfarina/uso terapéutico , Anciano , Anticoagulantes/efectos adversos , Anticoagulantes/farmacocinética , Población Negra/genética , Brasil , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Grupos Raciales/genética , Warfarina/efectos adversos , Warfarina/farmacocinética , Población Blanca/genética

RESUMEN

INTRODUCTION: In the search to prevent hemorrhages associated with anticoagulant therapy, a major goal is to validate predictors of sensitivity to warfarin. However, previous studies in Colombia that included polymorphisms in the VKORC1 and CYP2C9 genes as predictors reported different algorithm performances to explain dose variations, and did not evaluate the prediction of sensitivity to warfarin.  OBJECTIVE: To determine the accuracy of the pharmacogenetic analysis, which includes the CYP2C9 *2 and *3 and VKORC1 1639G>A polymorphisms in predicting patients' sensitivity to warfarin at the Hospital Militar Central, a reference center for patients born in different parts of Colombia.  MATERIALS AND METHODS: Demographic and clinical data were obtained from 130 patients with stable doses of warfarin for more than two months. Next, their genotypes were obtained through a melting curve analysis. After verifying the Hardy-Weinberg equilibrium of the genotypes from the polymorphisms, a statistical analysis was done, which included multivariate and predictive approaches.  RESULTS: A pharmacogenetic model that explained 52.8% of dose variation (p<0.001) was built, which was only 4% above the performance resulting from the same data using the International Warfarin Pharmacogenetics Consortium algorithm. The model predicting the sensitivity achieved an accuracy of 77.8% and included age (p=0.003), polymorphisms *2 and *3 (p=0.002) and polymorphism 1639G>A (p<0.001) as predictors.  CONCLUSIONS: These results in a mixed population support the prediction of sensitivity to warfarin based on polymorphisms in VKORC1 and CYP2C9 as a valid approach in Colombian patients.

Asunto(s)

Anticoagulantes/farmacocinética , Citocromo P-450 CYP2C9/genética , Polimorfismo de Nucleótido Simple , Vitamina K Epóxido Reductasas/genética , Warfarina/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Alelos , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Colombia , Relación Dosis-Respuesta a Droga , Etnicidad/genética , Femenino , Estudios de Asociación Genética , Geografía Médica , Hemorragia/inducido químicamente , Hemorragia/prevención & control , Humanos , Relación Normalizada Internacional , Masculino , Persona de Mediana Edad , Warfarina/administración & dosificación , Warfarina/efectos adversos

RESUMEN

Introducción. La validación de los factores predictores de la sensibilidad a la warfarina es importante para evitar las hemorragias asociadas con la terapia anticoagulante. En los estudios previos hechos en Colombia con polimorfismos de los genes VKORC1 y CYP2C9 , se reportaban algoritmos con rendimientos diferentes para explicar la variación de las dosis, pero no se evaluaba la predicción de la sensibilidad a la warfarina. Objetivo. Determinar la exactitud del análisis farmacogenético de los polimorfismos *2 y *3 en el gen CYP2C9 y 1639G>A en el gen VKORC1 para predecir la sensibilidad a la warfarina en pacientes del Hospital Militar Central, un centro de referencia que atiende pacientes de diferentes lugares de Colombia. Materiales y métodos. Se recopilaron los datos demográficos y clínicos de 130 pacientes que habían recibido una dosis estable de warfarina durante más de dos meses. Se obtuvieron sus genotipos mediante un análisis de curvas de fusión , y, después de verificar el equilibrio de Hardy-Weinberg de los polimorfismos, se hizo un análisis estadístico con enfoque multivariado y predictivo. Resultados. Se construyó un modelo farmacogenético que explicó el 52,8 % de la variación de la dosis (p<0,001), solo 4 % por encima del rendimiento obtenido con los mismos datos usando el algoritmo del International Warfarin Pharmacogenetics Consortium . El modelo predictivo de sensibilidad logró 77,8 % de exactitud e incluyó como factores la edad (p=0,003), los polimorfismos *2 y *3 (p=0,002) y el polimorfismo 1639G>A (p<0,001). Conclusiones. Estos resultados en una población mestiza colombiana respaldan la validez de la predicción de la sensibilidad a la warfarina basada en los polimorfismos de los genes VKORC1 y CYP2C9.

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Introduction: In the search to prevent hemorrhages associated with anticoagulant therapy, a major goal is to validate predictors of sensitivity to warfarin. However, previous studies in Colombia that included polymorphisms in the VKORC1 and CYP2C9 genes as predictors reported different algorithm performances to explain dose variations, and did not evaluate the prediction of sensitivity to warfarin. Objective: To determine the accuracy of the pharmacogenetic analysis, which includes the CYP2C9 *2 and *3 and VKORC1 1639G>A polymorphisms in predicting patients´ sensitivity to warfarin at the Hospital Militar Central , a reference center for patients born in different parts of Colombia. Materials and methods: Demographic and clinical data were obtained from 130 patients with stable doses of warfarin for more than two months. Next, their genotypes were obtained through a melting curve analysis. After verifying the Hardy-Weinberg equilibrium of the genotypes from the polymorphisms, a statistical analysis was done, which included multivariate and predictive approaches. Results: A pharmacogenetic model that explained 52.8% of dose variation (p<0.001) was built, which was only 4% above the performance resulting from the same data using the International Warfarin Pharmacogenetics Consortium algorithm. The model predicting the sensitivity achieved an accuracy of 77.8% and included age (p=0.003), polymorphisms *2 and *3 (p=0.002) and polymorphism 1639G>A (p<0.001) as predictors. Conclusions: These results in a mixed population support the prediction of sensitivity to warfarin based on polymorphisms in VKORC1 and CYP2C9 as a valid approach in Colombian patients.

Asunto(s)

Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Warfarina/farmacocinética , Polimorfismo de Nucleótido Simple , Vitamina K Epóxido Reductasas/genética , Citocromo P-450 CYP2C9/genética , Anticoagulantes/farmacocinética , Warfarina/administración & dosificación , Warfarina/efectos adversos , Algoritmos , Etnicidad/genética , Colombia , Relación Normalizada Internacional , Relación Dosis-Respuesta a Droga , Alelos , Estudios de Asociación Genética , Geografía Médica , Hemorragia/inducido químicamente , Hemorragia/prevención & control , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos

RESUMEN

Introducción: la eficacia terapéutica y seguridad de la warfarina en prevención de trombosis en pacientes con fibrilación auricular (FA)/flutter y/o prótesis valvulares depende del adecuado nivel de anticoagulación, valorado mediante mediante la relación normalizada internacional o international normalized ratio (INR) (INR). El porcentaje de tiempo en rango terapéutico (TRT) valora la calidad de la anticoagulación con warfarina y se vincula inversamente con la incidencia de complicaciones trombóticas o hemorrágicas. Objetivos: valorar la calidad de anticoagulación oral con warfarina a través del análisis del TRT en la policlínica de cardiología. Identificar factores asociados a un adecuado nivel de anticoagulación (TRT ³ 65%). Material y método: estudio retrospectivo, observacional y analítico de una cohorte de 117 pacientes anticoagulados con warfarina entre el 1º de junio de 2012 y el 31 de julio de 2013. El TRT individual se calculó mediante método de Rosendaal (interpolación lineal). Las variables analizadas fueron: edad, sexo, indicación de anticoagulación, nivel de instrucción, grado de adherencia, situación familiar, comorbilidades y número de fármacos concomitantes. Resultados: la media de edad fue de 67 ± 14 años, sexo femenino 62%, anticoagulación por FA 63% y por válvula mecánica 37%. La media de TRT fue de 56,6%. Solo el 38% de los pacientes tuvieron una media de TRT adecuada (³ 65%) y esta se asoció de forma positiva a un rango etario entre 50-74 años (70,5%) (p = 0,04) y al uso concomitante de tres o más fármacos (79,5%) (p = 0,044). Conclusión: la media de TRT estuvo por debajo del nivel definido como adecuada calidad de anticoagulación. Una adecuada anticoagulación se asoció a menor edad y uso de tres o más fármacos. Estos resultados constituyen la base para el desarrollo de estrategias futuras para una mejor asistencia.

Asunto(s)

Humanos , Masculino , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anticoagulantes , Warfarina/farmacocinética , Relación Normalizada Internacional , Trombosis/prevención & control , Administración Oral , Warfarina/uso terapéutico

RESUMEN

Introducción: la eficacia terapéutica y seguridad de la warfarina en prevención de trombosis en pacientes con fibrilación auricular (FA)/flutter y/o prótesis valvulares depende del adecuado nivel de anticoagulación, valorado mediante mediante la relación normalizada internacional o international normalized ratio (INR) (INR). El porcentaje de tiempo en rango terapéutico (TRT) valora la calidad de la anticoagulación con warfarina y se vincula inversamente con la incidencia de complicaciones trombóticas o hemorrágicas. Objetivos: valorar la calidad de anticoagulación oral con warfarina a través del análisis del TRT en la policlínica de cardiología. Identificar factores asociados a un adecuado nivel de anticoagulación (TRT ³ 65%). Material y método: estudio retrospectivo, observacional y analítico de una cohorte de 117 pacientes anticoagulados con warfarina entre el 1º de junio de 2012 y el 31 de julio de 2013. El TRT individual se calculó mediante método de Rosendaal (interpolación lineal). Las variables analizadas fueron: edad, sexo, indicación de anticoagulación, nivel de instrucción, grado de adherencia, situación familiar, comorbilidades y número de fármacos concomitantes. Resultados: la media de edad fue de 67 ± 14 años, sexo femenino 62%, anticoagulación por FA 63% y por válvula mecánica 37%. La media de TRT fue de 56,6%. Solo el 38% de los pacientes tuvieron una media de TRT adecuada (³ 65%) y esta se asoció de forma positiva a un rango etario entre 50-74 años (70,5%) (p = 0,04) y al uso concomitante de tres o más fármacos (79,5%) (p = 0,044). Conclusión: la media de TRT estuvo por debajo del nivel definido como adecuada calidad de anticoagulación. Una adecuada anticoagulación se asoció a menor edad y uso de tres o más fármacos. Estos resultados constituyen la base para el desarrollo de estrategias futuras para una mejor asistencia.

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Background: the efficacy and safety of warfarin in preventing thrombosis in patients with atrial fibrillation/flutter or prosthetic valves depends on adequate anticoagulation levels expressed as INR (International Randomized Ratio). The percentage of time in therapeutic range (TTR) assesses the quality of warfarin anticoagulation and is inversely associated with the presence of thrombotic or hemorrhagic complications. Objective: to assess the quality of anticoagulation through analysis of TTR. Identify factors associated with an adequate level of anticoagulation (TTR³65%). Method: observational, retrospective and analytic study of a cohort of 117 patients anticoagulated with warfarin from June 1, 2012 to July 31, 2013. The individual TTR was calculated using Rosendaal method (linear interpolation). The variables analyzed were age, sex, indication for anticoagulation, level of education, degree of adherence, family status, comorbidities and number of concomitant drugs. X² test was used for statistical analysis of categorical variables. Result: mean age was 67 ± 14 years, 62 % were female and indication for anticoagulation was FA in 63% and mechanical valve in 37% of patients. The mean TTR was 56,6%. Only 38% had an adequate TTR and it was associated with age between 50-74 years (70.5%) (p=0,04) and concomitant use of 3 or more drugs (79.5%) (p=0,044). Conclusion: The mean TTR was below the value defined as good control. Better control was associated with younger age and use of three or more drugs. These results support the development of strategies for a better quality of assistance.

Asunto(s)

Humanos , Masculino , Adulto , Trombosis/prevención & control , Warfarina/farmacocinética , Relación Normalizada Internacional , Anticoagulantes , Warfarina/uso terapéutico , Administración Oral

RESUMEN

Warfarin is among the ten drugs most commonly involved in adverse drug reactions, has a narrow therapeutic index and complex dosage regimen, exhibits enormous variability dose-response and high risk drug-drug interactions. To analyze the profile of pharmacoepidemiological drug prescriptions for warfarin in patients admitted to a Brazilian tertiary hospital. In the cross sectional study the electronic prescriptions of the January 01, 2004-December 31, 2010 of patients using warfarin of the Clinical Hospital of the Faculty of Medicine of Ribeirao Preto were analyzed. Sociodemographic characteristics, clinical data, laboratory test results, and drug therapy data were collected. We identified 3,048 patients who received 154,161 drug prescriptions, 42,120 of which contained warfarin. The mean age was 55.8 ± 19.3 years, 48.2% were elderly, and 4.3% had specific cerebrovascular disease diagnoses. The average International Normalized Ratio (INR; 2.4 ± 1.7) and warfarin dose (5.1 ± 1.8 mg/day) were within therapeutic protocol recommendations. However, approximately 14.0 and 8.5% of the patients had mean INR greater than 3.0 and 3.5, respectively. In addition, 66.4 and 6.1% of the patients received polypharmacy and clopidogrel, respectively, which can increase the risk of drug-drug interactions and bleeding. The average number of drugs per prescription was 7.2 ± 3.8, and 31,595 drug prescriptions (74.0%) consisted of five or more drugs. The study found a high prevalence of elderly patients, polypharmacy, and concomitant use of anticoagulant and antiplatelet drugs, which may favor the occurrence of adverse events.

Asunto(s)

Anticoagulantes , Bases de Datos Factuales , Relación Normalizada Internacional , Warfarina , Adulto , Anciano , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Anticoagulantes/farmacocinética , Brasil/epidemiología , Clopidogrel , Estudios Transversales , Relación Dosis-Respuesta a Droga , Incompatibilidad de Medicamentos , Femenino , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Hemorragia/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Farmacoepidemiología/métodos , Prevalencia , Factores Socioeconómicos , Centros de Atención Terciaria , Ticlopidina/administración & dosificación , Ticlopidina/efectos adversos , Ticlopidina/análogos & derivados , Ticlopidina/farmacocinética , Warfarina/administración & dosificación , Warfarina/efectos adversos , Warfarina/farmacocinética

RESUMEN

OBJECTIVES: The main aim of this study was to determine whether CYP2C9 and VKORC1 polymorphisms influence warfarin dose variability during initial dose-finding phase and during maintenance treatment after 360 days. METHODS: Two hundred and six consecutive patients who were beginning warfarin therapy were selected. They were assessed for general and clinical characteristics; prescribed warfarin dose; response to therapy on days 7-10, 30, 60, 180, and 360; adverse events; and CYP2C9 2, 3, 5, 6, 8, 11, and VKORC1 1639G >A assays. RESULTS: During the first 30 days of anticoagulation, the relative variability of warfarin dose was significantly associated with CYP2C9*2 and CYP2C9*3 polymorphisms (p = 0.02) and with VKORC1 1639G >A genotypes (p = 0.04). Warfarin variability was also statistically different according to predicted metabolic phenotype and to VKORC1 genotypes after 360 days of treatment, and in the phase between 180 and 360 days (long-term dose variability). Both CYP2C9 and VKORC1 polymorphisms were associated with the international normalized ratio (INR) made between 7 and 10 days/initial dose ratio, adjusted for covariates (p < 0.01 and p = 0.02, respectively). Patients carrying VKORC1 and CYP2C9 variants presented lower required dose (at the end of follow-up of 360 days) compared to patients carrying wild-type genotypes (p = 0.04 and p = 0.03, respectively). CONCLUSIONS: Genetic information on CYP2C9 and VKORC1 is important both for the initial dose-finding phase and during maintenance treatment with warfarin.

Asunto(s)

Anticoagulantes/administración & dosificación , Hidrocarburo de Aril Hidroxilasas/genética , Coagulación Sanguínea/efectos de los fármacos , Oxigenasas de Función Mixta/genética , Polimorfismo Genético , Warfarina/administración & dosificación , Anticoagulantes/efectos adversos , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Citocromo P-450 CYP2C9 , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Tiempo , Vitamina K Epóxido Reductasas , Warfarina/efectos adversos , Warfarina/farmacocinética , Warfarina/farmacología

RESUMEN

Oral anticoagulants are among the drugs with the greatest number of drug interactions. The concomitant use of several medications is a common practice in patients with cardiovascular problems, who often also present with depression; therefore, the probability of an interaction occurring between warfarin and the antidepressants is high, and may result in increased or decreased anticoagulant activity. Since the possible interactions between these two classes of drugs have been poorly explored in literature, with a risk to the patients who use them, we reviewed the pharmacology of warfarin and its possible interactions with antidepressants. Of the antidepressants analyzed, those that showed relevant effects on the interaction with warfarin were, in decreasing order: paroxetine, venlafaxine, fluoxetine, and duloxetine.

Asunto(s)

Anticoagulantes/farmacología , Antidepresivos/farmacología , Warfarina/farmacología , Administración Oral , Anticoagulantes/efectos adversos , Anticoagulantes/farmacocinética , Anticoagulantes/uso terapéutico , Biotransformación/efectos de los fármacos , Ciclohexanoles/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Interacciones Farmacológicas , Clorhidrato de Duloxetina , Fluoxetina/farmacología , Hemorragia/inducido químicamente , Humanos , Paroxetina/farmacología , Tiofenos/farmacología , Trombofilia/tratamiento farmacológico , Clorhidrato de Venlafaxina , Vitamina K/antagonistas & inhibidores , Warfarina/efectos adversos , Warfarina/farmacocinética , Warfarina/uso terapéutico

RESUMEN

Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA-approved oral anticoagulants will be evaluated.

Asunto(s)

Anticoagulantes/administración & dosificación , Antitrombinas/administración & dosificación , Formularios de Hospitales como Asunto , Administración Oral , Anticoagulantes/farmacocinética , Antitrombinas/farmacocinética , Benzamidas/administración & dosificación , Benzamidas/farmacocinética , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Dabigatrán , Humanos , Morfolinas/administración & dosificación , Morfolinas/farmacocinética , Pennsylvania , Pirazoles/administración & dosificación , Pirazoles/farmacocinética , Piridinas/administración & dosificación , Piridinas/farmacocinética , Piridonas/administración & dosificación , Piridonas/farmacocinética , Rivaroxabán , Tiofenos/administración & dosificación , Tiofenos/farmacocinética , Warfarina/administración & dosificación , Warfarina/farmacocinética , beta-Alanina/administración & dosificación , beta-Alanina/análogos & derivados , beta-Alanina/farmacocinética

RESUMEN

Oral anticoagulants are among the drugs with the greatest number of drug interactions. The concomitant use of several medications is a common practice in patients with cardiovascular problems, who often also present with depression; therefore, the probability of an interaction occurring between warfarin and the antidepressants is high, and may result in increased or decreased anticoagulant activity. Since the possible interactions between these two classes of drugs have been poorly explored in literature, with a risk to the patients who use them, we reviewed the pharmacology of warfarin and its possible interactions with antidepressants. Of the antidepressants analyzed, those that showed relevant effects on the interaction with warfarin were, in decreasing order: paroxetine, venlafaxine, fluoxetine, and duloxetine.

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Os anticoagulantes orais estão entre as drogas com maior número de interações medicamentosas. O uso concomitante de vários medicamentos é uma prática comum em pacientes com problemas cardiovasculares, os quais frequentemente também apresentam depressão; assim, a probabilidade de ocorrer alguma interação entre a varfarina e os antidepressivos é bem expressiva, podendo resultar em um aumento ou uma diminuição da atividade anticoagulante. Como as possíveis interações entre essas duas classes de medicamentos se mostraram pouco exploradas na literatura, com risco aos pacientes que fazem uso delas, revisamos a farmacologia da varfarina e suas possíveis interações com antidepressivos. Dos antidepressivos analisados, os que apresentaram efeitos relevantes na interação com a varfarina foram, em ordem decrescente: paroxetina, venlafaxina, fluoxetina e duloxetina.

Asunto(s)

Humanos , Anticoagulantes/farmacología , Antidepresivos/farmacología , Warfarina/farmacología , Administración Oral , Anticoagulantes/efectos adversos , Anticoagulantes/farmacocinética , Anticoagulantes/uso terapéutico , Biotransformación/efectos de los fármacos , Ciclohexanoles/farmacología , /metabolismo , Interacciones Farmacológicas , Fluoxetina/farmacología , Hemorragia/inducido químicamente , Paroxetina/farmacología , Tiofenos/farmacología , Trombofilia/tratamiento farmacológico , Vitamina K/antagonistas & inhibidores , Warfarina/efectos adversos , Warfarina/farmacocinética , Warfarina/uso terapéutico

RESUMEN

Warfarin is the most utilized oral anticoagulant for the long term prophylaxes of thrombosis. Its use has been increased as new clinical conditions, capable of leading to thrombosis, have been detected. Due to the special characteristics of warfarin, such as the variability of doses for each individual, the narrow margin between adequate and inadequate doses, interaction with multiple pharmaceutical products, interference of its action by vitamin K present in the diet and the possibility of hemorrhagic complications or thrombotic recurrence, this drug requires a very careful dosage and strict laboratory and clinical monitoring. Despite being in the market for more than de fifty years and its many disadvantages, warfarin has not been substituted for the new oral anticoagulants. In 1999, warfarin was positioned eleventh on the list of the most used medicines in the world.

Asunto(s)

Anticoagulantes/historia , Warfarina/historia , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Anticoagulantes/farmacocinética , Anticoagulantes/uso terapéutico , Interacciones Farmacológicas , Monitoreo de Drogas , Interacciones Alimento-Droga , Hemorragia/inducido químicamente , Hemorragia/tratamiento farmacológico , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Relación Normalizada Internacional , Oxigenasas de Función Mixta/antagonistas & inhibidores , Educación del Paciente como Asunto , Trombofilia/tratamiento farmacológico , Trombosis/prevención & control , Vitamina K/metabolismo , Vitamina K/uso terapéutico , Vitamina K Epóxido Reductasas , Warfarina/administración & dosificación , Warfarina/efectos adversos , Warfarina/farmacocinética , Warfarina/uso terapéutico

RESUMEN

Warfarin is the most prescribed oral anticoagulant worldwide. Because of the complexity of warfarin therapy, we attempted to dissect genetic from bioenvironmental factors influencing warfarin dose responses in individuals of a genetic isolate of Hispanic ancestry. A total of 191 patients with standard values of international normalized ratio were recruited. Three groups with a significantly different warfarin dose response were identified, that is, sensitive (2.28 +/- 0.50 mg/d), intermediate (4.2 +/- 0.76 mg/d), and resistant (7.40 +/- 1.54 mg/d; Tukey test, P < .001). Age had a significant inverse correlation with warfarin dose (P < .001; effective dose diminished 0.56 mg/d/decade). Required doses were higher for individuals with CYP2C9 variants containing the allele *1 compared to those individuals with variants composed of other alleles (P = .006). Similarly, individuals with VKORC1-1639GG and VKORC1-1639GA genotypes also required higher doses compared to the AA genotype (P < .001). Evaluation of potential gene-gene interactions between CYP2C9 and VKORC1 polymorphisms showed significant differences in dosing for CYP2C9 genotypes within the VKORC1-1639G/A subgroup (P = .013). A stepwise multivariate linear regression analysis showed that 38.2% of the warfarin dose response variance was accounted for by a model involving age (20.9%), VKORC1-1639G/A (11.3%), and CYP2C9*1, *2, and *3 variants (7.1%). These results corroborate previous findings on warfarin pharmacogenetics and define a contrastable gene-bioenvironment interaction model suited to be used in Hispanic populations.

Asunto(s)

Anticoagulantes/administración & dosificación , Hidrocarburo de Aril Hidroxilasas/genética , Oxigenasas de Función Mixta/genética , Trombosis , Warfarina/administración & dosificación , Adulto , Anciano , Anticoagulantes/farmacocinética , Colombia/epidemiología , Citocromo P-450 CYP2C9 , Relación Dosis-Respuesta a Droga , Etnicidad/estadística & datos numéricos , Femenino , Frecuencia de los Genes , Variación Genética , Genotipo , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Trombosis/etnología , Trombosis/genética , Trombosis/prevención & control , Vitamina K Epóxido Reductasas , Warfarina/farmacocinética

RESUMEN

PURPOSE: To explore the pharmacogenomics of warfarin using the extreme-discordant-phenotype (EDP) methodology. METHODS: The target phenotype was the stable warfarin dose prescribed to 353 patients. Pharmacogenetic polymorphisms assessed were coagulation factor VII (FVII) -401G>T and FVII -402G>A, VKORC1 3673G>A, and CYP2C9*2, *3, *5, and *11 alleles. The EDP analyses contrasted the frequencies of these polymorphisms at different cutoff points (5th through 30th percentiles of the warfarin dose distribution) at opposite ends of the warfarin dose distribution. RESULTS: Significant differences existed in FVII -402G>A genotype frequency at the 5th percentile with an over-representation of the wildtype GG genotype at low warfarin doses and in VKORC1 3673G>A and CYP2C9 polymorphisms at all cutoff points where the variant alleles were overrepresented at low warfarin doses. CONCLUSION: The EDP methodology provides increased statistical power for detection of small contributions of genetic polymorphisms to multiple drug-response phenotypes, such as warfarin dose requirement for adequate anticoagulation.

Asunto(s)

Anticoagulantes/farmacocinética , Hidrocarburo de Aril Hidroxilasas/genética , Factor VII/genética , Oxigenasas de Función Mixta/genética , Farmacogenética/métodos , Polimorfismo de Nucleótido Simple , Warfarina/farmacocinética , Adulto , Anticoagulantes/administración & dosificación , Población Negra/genética , Brasil , Citocromo P-450 CYP2C9 , Femenino , Humanos , Masculino , Fenotipo , Polimorfismo Genético , Estudios Retrospectivos , Vitamina K Epóxido Reductasas , Warfarina/administración & dosificación , Población Blanca/genética

RESUMEN

Noncoding polymorphisms in the VKORC1 gene associate with variation of interindividual dosing requirements of warfarin and other coumarin anticoagulants. The frequency of VKORC1 polymorphisms displays distinct interpopulation differences. Here, we report the distribution of the VKORC1 3673G>A, 5808T>G, 6853G>C and 9041G>A SNPs in three endogamous Amerindian (Native American) populations, namely, Guarani-Kaiowá, Guarani-Nandeva and Kaingang. Individual DNA from 180 healthy adults was genotyped for the VKORC1 polymorphisms using TaqMan Detection System assays. The ARLEQUIN 3.1 software package was used to estimate haplotype frequency and linkage disequilibrium. The VKORC1 3673G>A, 5808T>G, 6853G>C and 9041G>A polymorphisms were in Hardy-Weinberg equilibrium in each population. The 5808G allele was absent or rare (<3%), whereas 3673A, 6853C and 9041A were frequent (34-63%) in the three Amerindian populations. No difference was detected in allele or genotype frequency bewteen the two Guarani populations, whereas significant differences were observed between Kaingang and Guarani. Polymorphisms 3673G>A, 6853G>C and 9041G>A were in significant linkage disequilibrium in both Guarani and Kaingang (pairwise r2 values: 0.77-1.0). Haplotypes ATCG and GTGA accounted for more than 94% of the haplotypes in both populations, ATCG being the most common in Guarani (49.5%) and GTGA in Kaingang (54%). These data disclose the uniqueness of the frequency distribution of the VKORC1 SNPs in the Amerindians, compared with Asian, African and European populations. In view of the vast interpopulational diversity among Amerindians, the present data should not be interpreted as representative of other extant Amerindian peoples. Our estimates that 40% of Kaingang and 60% of Guarani have haplotypes including the variant 3673A allele suggest that these two Amerindian populations comprise high proportions of individuals requiring reduced warfarin doses.

Asunto(s)

Genética de Población , Indígenas Sudamericanos/genética , Oxigenasas de Función Mixta/genética , Polimorfismo de Nucleótido Simple , Brasil , Frecuencia de los Genes , Haplotipos , Humanos , Desequilibrio de Ligamiento , Vitamina K Epóxido Reductasas , Warfarina/farmacocinética