Uso inadecuado del fármaco acenocumarol en la fibrilación auricular no valvular

Introducción: El uso del acenocumarol como anticoagulante, constituye un aporte al tratamiento de la fibrilación auricular no valvular. En la actualidad existen otros tipos de anticoagulantes que no requieren control tan exhaustivo de la prueba digital International Normaizedl Ratio y tienen menos efectos secundarios. España es uno de los pocos países de Europa que continúa indicando acenocumarol, de forma similar a la warfarina. Tanto es así, que a los médicos de atención primaria no se les permite prescribir otros anticoagulantes más eficaces y menos molestos, para el paciente al realizar la prueba digital. Objetivo: Analizar el uso inadecuado del fármaco acenocumarol en la fibrilación auricular no valvular. Métodos: Se realizó un estudio exploratorio, en un sistema de salud de atención primaria y hospitales de categoría secundaria. La población la integraron 2 650 habitantes del sureste español con fibrilación auricular no valvular, tomadores de acenocumarol con seguimiento de 12 meses. Resultados: Se consideró las variaciones y labilidad del valor International Normalized Ratio, entre 2,0-3,0 en determinaciones cada 28 días, no obstante a la enfermedad cardiovascular y cifras obtenidas respecto a las anteriores. El tiempo de seguimiento fue 12 meses y desapareció la fragilidad, se tomaron muestras cada 28 días. Antes de finalizar el estudio, desapareció la labilidad del International Normalized Ratio durante más de tres meses en 53 (97,95 %) de los pacientes. Dado que la mayoría de los enfermos que consumían acenocumarol tenían edades por encima de 65 años y estaban sometidos a régimen de poli medicación, los medicamentos que consumían, fueron motivo de evaluación. Conclusiones: El tiempo transcurrido entre la determinación del International Normaizedl Ratio y la última ingesta de alimentos y medicamentos, no fue correcto, existe tendencia a realizar determinaciones anárquicas del International Normalized Ratio, sin investigaciones relacionadas con fármacos consumidos junto al acenocumarol.

Introduction: The use of acenocoumarol as an anticoagulant represents a contribution to the treatment of non-valvular atrial fibrillation. At present, there are other types of anticoagulants that do not require such exhaustive control of the International Normalized Ratio digital test and have fewer side effects. Spain is one of the few countries in Europe that continues to prescribe acenocoumarol, which is similar to warfarin. So much so that primary care physicians are not allowed to prescribe other more effective and less troublesome anticoagulants for the patient when performing the digital test. Objective: To analyze the inappropriate use of the drug acenocoumarol in non-valvular atrial fibrillation. Methods: An exploratory study was carried out in a primary health care system and secondary category hospitals. The population consisted of 2650 inhabitants of southeastern Spain with non-valvular atrial fibrillation, taking acenocoumarol with 12 months follow-up. Results: We considered the variations and lability of the International Normalized Ratio value, between 2.0-3.0 in determinations every 28 days, regardless of cardiovascular disease and figures obtained in relation to the previous. The follow-up time was 12 months and the lability disappeared, samples were taken every 28 days. Before the end of the study, the lability of the International Normalized Ratio disappeared for more than three months in 53 (97.95%) of the patients. Since most of the patients taking acenocoumarol were over 65 years of age and on polymedication, the medications taken by each of them were evaluated. Conclusions: The time elapsed between the International Normalized Ratio determination and the last intake of food and medication was not correct, and there is a tendency to perform anarchic determinations of the International Normalized Ratio without investigations related to drugs consumed together with acenocoumarol.

Estudio del desempeño analítico del dispositivo portátil microINR en pacientes anticoagulados con acenocumarol / Analytical performance of the microINR portable device in acenocoumarol anticoagulated patients

Resumen La razón internacional normalizada (RIN) se utiliza para controlar a los pacientes anticoagulados con antagonistas de la vitamina K. El objetivo de este estudio fue evaluar el desempeño del nuevo dispositivo portátil microINR, que utiliza tromboplastina recombinante, en pacientes anticoagulados con acenocumarol. Grupo 1: los pacientes proporcionaron muestras de sangre venosa y capilar para realizar pruebas paralelas que permitieron comparar microINR con cinco combinaciones diferentes de reactivo/sistema de detección: tromboplastina de cerebro de conejo con detección nefelométrica, foto-óptica y por viscosidad y tromboplastina humana recombinante con detección nefelométrica y fotoóptica. Todas las tromboplastinas tenían un índice de sensibilidad internacional (ISI) específico de equipo informado por el fabricante menor de 1,10. Grupo 2: los resultados de microINR se compararon con CoaguChek como dispositivo preestablecido. La precisión se evaluó utilizando materiales de control líquidos. El coeficiente de variación del material de control en microINR fue de 6,2%. El análisis de regresión de Passing-Bablok y Bland-Altman mostró un coeficiente de correlación superior a 0,92 y un pequeño sesgo cercano a cero para todas las comparaciones de microINR con cada método tradicional realizado con sangre venosa. Ambos dispositivos portátiles tuvieron un muy buen coeficiente de correlación (r=0,98) y un pequeño sesgo de 0,02. Los resultados muestran un acuerdo clínico del 100% con un grado de concordancia Kappa mayor de 0,63 para todos los métodos tradicionales y de 0,82 para la comparación con Coagu- Chek. De acuerdo a los resultados obtenidos, el microINR es adecuado para el control de pacientes anticoagulados con acenocumarol.

Abstract The international normalised ratio (INR) is used to monitor vitamin K antagonist anticoagulated patients. The aim of this study was to evaluate the performance of the microINR portable device in acenocoumarol anticoagulated patients. Group 1: patients provided capillary and venous blood samples for parallel testing comparing microINR with five different pairs of reagent/clot detection systems: brain rabbit thromboplastin with nephelometric, photooptic and viscocity clot detection and recombinant human thromboplastin with nephelometric and photooptical detection. All thromboplastins have an instrument-specific International Sensitivity Index (ISI) lower than 1.10 reported by the manufacturer. Group 2: microINR results were compared with CoaguChek as an established device. Precision was assessed using liquid control materials. The control material coefficient of variation obtained in microINR device was 6.2%. The Passing-Bablok and Bland-Altman regression analysis showed a correlation coefficient greater than 0.92 and a small bias close to zero for all comparisons of microINR with each traditional coagulation method performed on venous blood samples. Both portable devices had a good correlation (r=0.98) and a very low bias of 0.02. The results show clinical agreement of 100% with a Kappa greater than 0.63 for different traditional INR and greater than 0.83 for CoaguChek. The performance microINR is suitable for the anticoagulation control of patients taking acenocumarol.

Resumo A razão normalizada internacional (INR) é utilizada para monitorar pacientes anticoagulados com antagonistas da vitamina K. O objetivo deste estudo foi avaliar o desempenho do dispositivo portátil microINR, um novo dispositivo que utiliza tromboplastina recombinante, em pacientes anticoagulados com acenocumarol. Grupo 1: os pacientes forneceram amostras de sangue venoso e capilar para testes paralelos que permitiram a comparação do microINR com cinco combinações diferentes de reagente/ sistema de detecção: tromboplastina de cérebro de coelho com detecção nefelométrica, foto-óptica e de viscosidade. Tromboplastina humana recombinante com detecção nefelométrica e foto-óptica. Todas as tromboplastinas tinham o Índice de Sensibilida de Internacional (ISI) específico do kit relatado pelo fabricante inferior a 1,10. Grupo 2: os resultados do microINR foram comparados com o CoaguChek como dispositivo padrão. A precisão foi avaliada usando materiais de controle líquidos. O coeficiente de variação do material de controle em microINR foi de 6,2%. A análise de regressão de Passing-Bablok e Bland-Altman mostrou um coeficiente de correlação maior que 0,92 e um pequeno viés próximo a zero para todas as variáveis. sangue. Ambos os wearables tiveram um coeficiente de correlação muito bom (r=0,98) e um pequeno viés de 0,02. Os resultados mostram 100% de concordância clínica com grau de concordância Kappa maior que 0,63 para todos os métodos tradicionais e 0,82 para a comparação com CoaguChek. De acordo com os resultados obtidos, o microINR é adequado para o controle de pacientes anticoagulados com acenocumarol.

Análisis farmacogenético retrospectivo de una paciente pediátrica en tratamiento anticoagulante: caso clínico / Retrospective pharmacogenetic analysis of a pediatric patient under anticoagulant treatment: Clinical case

Se presenta el caso clínico de una paciente de 10 años diagnosticada con miocardiopatía dilatada, quien registró valores en el índice internacional normalizado (International Normalized Ratio, INR) superiores a 10 con la dosis estándar de acenocumarol, además de otros valores que indicaban el estado incoagulable, lo que obligó a suspender y reiniciar el tratamiento en varias ocasiones. Después de más de 30 días de tratamiento, sorprendentemente se lograron los niveles esperados y estables en el INR con la mitad de la dosis recomendada para una paciente de su edad y peso.Se decidió hacer un análisis farmacogenético retrospectivo del caso mediante RT-PCR con sondas TaqMan™ que incluyó cinco polimorfismos de un solo nucleótido y distinto grado de asociación con la dosis-respuesta a los fármacos antivitamínicos K (AVK): rs2108622 (gen CYP4F2), rs9923231, rs7294 (gen VKORC1), rs1799853 y rs1057910 (gen CYP2C9). La paciente resultó ser homocigota para el rs9923231 (VKORC1) y heterocigota para el rs2108622 (CYP4F2). Se ha evidenciado a nivel nacional e internacional que este perfil genético está fuertemente asociado con una necesidad de dosis menores de antivitamínicos K.En conclusión, el análisis farmacogenético confirmó que la condición genética de la paciente, la cual conlleva una baja expresión de la enzima VKORC1 (blanco terapéutico de los antivitamínicos K), hacía predecible la necesidad de una dosis menor a la establecida según los protocolos clínicos recomendados por la Food and Drug Administration (FDA) y PharmGKB™ para los fármacos cumarínicos. El análisis genotípico previo de la paciente hubiese permitido alcanzar el rango terapéutico más prontamente, evitando potenciales riesgos de hemorragia, lo que demuestra la importancia de los análisis farmacogenéticos en tratamientos de gran variabilidad y estrecho rango terapéutico.

Abstract We present the clinical case of a 10-year-old patient diagnosed with dilated cardiomyopathy who registered INR values above 10 upon receiving standard doses of acenocoumarol, as well as other values reported as uncoagulable, forcing the discontinuation and restart of treatment more than once. Expected and stable INR levels were achieved after more than 30 days of treatment, surprisingly with half the recommended dose for a patient of her age and weight. We decided to conduct a retrospective pharmacogenomic analysis including nucleotide genetic polymorphisms (SNPs) with different degrees of association with the dose/response to antivitamin K (AVK) drugs: rs2108622 (gene CYP4F2), rs9923231, rs7294 (gene VKORC1), rs1799853, and rs1057910 (CYP2C9 gene) using TaqMan® RT-PCR. The patient was homozygous for rs9923231 (VKORC1) and heterozygous for rs2108622 (CYP4F2), a genetic profile strongly associated with a requirement of lower AVK doses as shown by national and international evidence. In conclusion, the pharmacogenetic analysis confirmed that this patient's genetic conditions, involving low expression of the VKA therapeutic target, required a lower dose than that established in clinical protocols as recommended by the Food and Drug Administration (FDA) and the PharmGKB® for coumarin drugs. A previous genotypic analysis of the patient would have allowed reaching the therapeutic range sooner, thus avoiding potential bleeding risks. This shows the importance of pharmacogenetic analyses for highly variable treatments with a narrow therapeutic range.

Impacto de la atención farmacéutica en la calidad del tratamiento con acenocumarol en pacientes con fibrilación auricular / Effects of pharmaceutical counseling on the effectiveness of anticoagulation in patients with atrial fibrillation

Background: Vitamin K antagonists such as acenocoumarol and warfarin are usually indicated for the treatment of Atrial Fibrillation (AF). The Therapeutic Range Time (TRT) is a quality of treatment indicator. Values greater than 65% are associated with significantly lower stroke and bleeding rates. Proper pharmaceutical care improves TRT. Aim: To evaluate the impact of pharmaceutical care in patients with AF treated with acenocoumarol. Material and Methods: We studied 41 patients using acenocoumarol for AF aged 71 ± 11 years (43% women). They received pharmaceutical counseling during 12 weeks. TRT was calculated retrospectively for the year before counseling and prospectively during the intervention period. Results: After receiving pharmaceutical counseling TRT improved from 29% at baseline to 46% at the end of the intervention (p < 0.01). After pharmaceutical care, the adherence of patients to drug treatment improved from 27% at baseline to 85% at the end of the study. The user satisfaction survey of the pharmaceutical care received showed a high degree of patient satisfaction. Conclusions: Pharmaceutical care in patients with oral anticoagulant treatment improves TRT of anticoagulation. It is accepted and positively evaluated by patients.

Eficacia en el control de la anticoagulación de los diferentes fármacos antagonistas de la vitamina K disponibles en Chile

Background: Vitamin K antagonist medications (VKA) are essential for the prevention of thromboembolic events, but their effectiveness is influenced by multiple factors, such as the type of medication chosen. Aim: To evaluate the efficacy in anticoagulant control of the bioequivalent and non-bioequivalent drugs of acenocoumarol compared to the reference drug. To evaluate the efficacy of warfarin bioequivalents available in Chile. To contrast the overall anticoagulant control efficacy between acenocoumarol and warfarin. Material and Methods: The results of 69333 outpatient oral anticoagulation controls were analyzed. Patient were separated in groups according to the drug that they used. Subsequently, the proportions of controls outside the range for each of acenocoumarol and warfarin bioequivalent drugs were compared. Acenocoumarol non-bioequivalent drugs were also compared with the reference drug. Acenocoumarol was compared with warfarin. Results: Acenocoumarol bioequivalent drugs and the reference drug had a similar proportion of controls outside the range (Odds ratios (OR) 0.812; 0.969; 0.974 and 0.963). Non-bioequivalent drugs had a higher proportion than the reference drug (OR 1.561 and 2.037). Both warfarin brands have a similar proportion of controls outside of the range (OR 1.050). Acenocoumarol compared to warfarin had a significant higher proportion of controls outside the range (OR 1.191). Conclusions: The pharmacological presentation of vitamin K antagonists could influence anticoagulant control. Therefore, it is not prudent to switch these presentations frequently.

Estudio comparativo de equipos INR capilar "point of care" versus INR venoso, en pacientes en tratamiento con antagonistas de vitamina K / Comparison of point of care capillary international normalized ratio (INR) with INR measured in venous samples

Background: INR is used to monitor the treatment with vitamin K antagonists. A strategy to reduce waiting times for sampling is to measure INR in a capillary sample using a portable point of care (POC) type coagulometer. Aim: To evaluate the correlation of CoaguChek Pro II™, Xprecia™ and microINR™ with venous INR measured at the clinical laboratory and their ease of use. Materials and Methods: Patients provided capillary and venous blood samples for parallel tests comparing Xprecia™ Stride with CoaguChek Pro II™ and with venous INR, microINR™ with CoaguChek Pro IITM and with venous INR. The devices' ease of use was assessed surveying the sampling staff. Results: The three tested devices had good correlation coefficients with venous INR: CoaguChek Pro IITM 0.953 and 0.962; Xprecia™ of 0.912 and microINR™ of 0.932. The correlation coefficient of Xprecia™ with CoaguChek Pro IITM was 0.937 and microINR™ with CoaguChek Pro IITM was 0.976. Conclusions: CoaguChek Pro IITM, Xprecia™ and microINR™ results had a good correlation coefficient with INR measured at the laboratory. Our results indicate that, in the hands of trained users, POC-type coagulometers are reliable and acceptable for routine use in anticoagulant treatment control.

Cross sectional study on different doses of acenocoumarol with INR in a tertiary care hospital

Background: It is of high value to be assess the relationship between doses of Acenocoumarol and the INR values to offer better patient care. Since Acenocoumarol is a commonly used drug with a narrow therapeutic range it is essential to monitor the variations encountered in response to it to avoid drastic complications and to provide better health care. Aim: The aim of this study is to compare the INR values with different doses of Acenocoumarol, to compare the association of dose of Acenocoumarol with their respective INR and to find out the occurrence of bleeding with different doses of Acenocoumarol.Methods: The study was conducted in a Tertiary care hospital. 40 patients taking Acenocoumarol were recruited in the study. Relevant details like age, weight, dose of Acenocoumarol, INR and other concomitant drugs were obtained in a prospective manner. Correlation of dose of Acenocoumarol with respective INR was done by simple linear regression.Results: The relationship between dose and INR was analyzed using Simple linear regression and the scatter plot revealed no significant correlation between the dose and INR values. There is a lot of inter-individual variability in the dose response and thereafter the INR values.Conclusions: The dose of Acenocoumarol cannot predict INR values. Patient can ideally be started treatment on a low dose of Acenocoumarol and based on the INR values, dose can be titrated. There is a need for consideration of other factors which influence the dose and INR values.

Rotura espontánea de bazo en paciente tratado con acenocumarol / Spontaneous rupture of spleen in a patient treated with acenocoumarol

Aunque la causa más frecuente de rotura esplénica es la traumática, podemos encontrar roturas sin relación a un traumatismo previo. Se está objetivando un aumento de roturas espontáneas en relación con tratamiento anticoagulante. Presentamos el caso de un hombre en tratamiento con acenocumarol que presentó una rotura espontánea esplénica que requirió esplenectomía urgente. La rotura de bazo es una entidad grave que debe considerarse ante todo paciente con un abdomen agudo. Aunque las causas más frecuentes de rotura esplénica atraumática son las complicaciones neoplásicas e infecciosas, se han objetivado varios casos asociados a terapias antiagregantes y anticoagulantes. Dado el aumento de población que precisa anticoagulación oral, la sobredosificación con acenocumarol debe considerarse como una posible causa de rotura esplénica. Debemos sospechar esta entidad ante todo paciente en tratamiento con anticoagulación oral con un abdomen agudo.

The splenic rupture is most commonly related to trauma, but spontaneus ruptures have also been described with increasing frequency. We present a case of a male patient with spontaneous splenic rupture due to oral anticoagulant overdose that required urgent splenectomy. The spontaneous splenic rupture is a life-threatening condition that must be considered in patients with acute abdomen. Although most ruptures are associated with to neoplastic and infectious complications , recent reports have related rupture with anticoagulant and antiaggregant therapies. Moreover, since the number of patients undergoing oral anticoagulant therapies is growing, overdose of anticoagulant drugs must be considered as a possible ethiology of spontaneous splenic rupture and suspect this association in patient with acute abdomen undergoing anticoagulant therapy.

Efectividad y seguridad del tratamiento anticoagulante con acenocumarol en fibrilación auricular no valvular / Effectiveness and safety of oral anticoagulation treatment with acenocoumarol in non-valvular atrial fibrillation

Background: Vitamin K antagonists significantly decrease the incidence of stroke but increase the risk of bleeding. Aim: To assess the effectiveness and risk of bleeding of vitamin K antagonists in non-valvular atrial fibrillation. Material and Methods: Retrospective cohort study of 524 patients, 236 women (45%) and 288 men (55%) with non-valvular atrial fibrillation (NVAF) admitted to the oral anticoagulation treatment (OAT) clinic at four public hospitals, between 2009 and 2012. They were followed until March 2013, measuring the quality of OAT, ischemic and bleeding events. Results: The mean follow-up was 26.1 months, with 1,154.7 person-years of follow-up accrued. The percentage of time in therapeutic range (TTR) was 35.2 ± 18%; this was deemed to represent the quality of OAT. The cumulative incidence of ischemic events, either stroke or systemic embolism, was 2.25/100 person-years, being greater in patients with previous embolism (Risk ratio 5.21, 95% confidence intervals 2.31- 11.73, p < 0.01). The cumulative incidence of major bleeding events-extracranial and intracraneal-was 4.08/100 person-years. The main site of extracranial major bleeding was the gastrointestinal tract (32%). Conclusions: In our clinical practice, the effectiveness of OAT with acenocoumarol in NVAF patients is similar to that published abroad. However, the incidence of bleeding complications is higher. The quality of the OAT measured by the TTR was lower than abroad.

Efecto de las variantes de VKORC1 y CYP2C9 sobre la dosis de anticoagulantes orales en individuos chilenos / Effect of VKORC1 and CYP2C9 variants on dosage of oral anticoagulants in Chilean individuals

Background: The dose of oral anticoagulants (OAC) shows great variability among patients. Pharmacogenetic studies have shown that common variants in genes CYP2C9 (*2 and *3) and VKORC1 (-1639G>A) are associated with lower requirements of OAC. Aim: To study the association between average maintenance doses of oral anticoagulant therapy required to maintain a stable INR and CYP2C9 and VKORC1 gene variants in Chilean adults. Material and Methods: Prospective study of patients on anticoagulant treatment and with a stable international normalized ratio (INR) for prothrombin time for at least three months. Patients were classified as having high or low acenocoumarol or warfarin requirements. Peripheral blood DNA genotyping was performed by polymerase chain reaction and restriction fragment polymorphism or sequencing and electrophoresis. Results: The study included 185 patients, 125 on acenocoumarol and 60 on warfarin. Patients with VKORC1-1639A allele were more likely to require lower doses of both drugs than patients with the G allele (Odds ratio [OR] for acenocoumarol 9.06, and OR for warfarin = 18.7). There was no association between CYP2C9*2 and*3 and acenocoumarol or warfarin requirements. Conclusions: There is an association between VKORC1-1639A variant and anticoagulant doses.

Calidad de las tromboplastinas utilizadas en el laboratorio clínico y en los equipos POCT y su impacto en la dosificación de acenocumarol en pacientes con terapia anticoagulante oral / Types of thromplastin used for INR determination in patients under chronic oral anticoagulant treatment: discrepancies that may affect the dose of coumarin derivatives needed for treatment safety

Antecedentes: El monitoreo del tratamiento con anticoagulantes cumarínicos se realiza a través del INR (International Normalized Ratio) que es el parámetro estandarizado del Tiempo de Protrombina. Las recomendaciones de la OMS indican que la precisión en el cálculo del INR puede ser mejorada usando reactivo de tromboplastina con Indice de Sensibilidad Internacional (ISI) bajo, considerándose como ISI de referencia internacional el valor 1,0. Debido a incongruencias observadas en los INR de pacientes controlados en el Servicio de Salud Metropolitano Occidente, comparando valores de muestra venosa con resultados de INR capilar obtenidos en el mismo paciente el mismo día y hora (con reactivos Tromboplastina de distinto ISI), se efectuó un ensayo clínico cruzado entre los distintos métodos. Materiales y métodos: En 100 pacientes se comparó INR venoso con dos tromboplastinas de diferente ISI (1,3 y 1,0) vs aquel efectuado con muestra capilar (ISI 1,0). Resultados: Los resultados del estudio muestran que a partir de valores de INR 3,0 las determinaciones obtenidas usando Tromboplastina de cerebro de conejo ISI=1,3 subestiman el valor de INR para un mismo paciente y una misma muestra. Conclusiones: El uso de Tromboplastina recombinante humana ISI 1,0 permite evitar la subestimación del INR en pacientes con mayor riesgo tromboembóli-co (indicación de INR objetivo más alto). Por ello, este método se adoptó en el control del TACO en pacientes controlados en el Servicio de Salud Occidente.

Background: INR (International Normalized Ratio) is the standard Prothrombin Time parameter for monitoring anticoagulant treatment with coumarin derivatives Recommendations of WHO indicate that precision in the calculation of the INR can be improved using thromboplastins with a low Index of International Sensibility (ISI=1,0). Discrepancies in INR obtained using either this technique or conventional rabbit brain derived reagents in the same sample in patients attending the Servicio de Salud Metropolitano Occidente (West Metropolitan Health Service) were observed. Our objective was to evaluate these discrepancies in a systematic way. Materials and methods: A comparative study was conducted using two thromboplastins of different ISI (1.0 and 1.3) for the calculation of venous INR in comparison with capillary INR in 100 patients. Results: The study showed that INR values may differ significantly according to the method used. In particular, rabbit brain thromboplastin ISI = 1.3 underestimates the value of INR in the range of INR ≥3.0. Conclusions: The use of human recombinant thromboplastin ISI= 1.0. for determination of INR may significantly decrease the risk of hemorrhagic complications in patients requiring higher levels of anticoagulation.

Dengue en un paciente anticoagulado

Presentamos un caso de un paciente de sexo masculino de 73 años de edad con dengue siendo portador de una prótesis mecánica en posición aórtica y anticoagulado con acenocumarol. Ingresó con plaquetopenia por lo que se suspendió acenocumarol y fue anticoagulado con enoxaparina. Evolucionó favorablemente por lo que fue dado de alta nuevamente con acenocumarol.

We present the case of a 73-year-old man with dengue who had a mechanical prosthesis in aortic position and was anticoagulated with acenocoumarol. As he was admitted with thrombocytopenia, acenocoumarol was suspended and anticoagulated instead with enoxaparin. The patient showed a favorable evolution and was discharged and restarted on acenocoumarol.

Influence of Vitamin K Epoxide Reductase Complex 1 Gene Polymorphisms on Anticoagulation with Acenocoumarol in Patients with Cerebral Venous Thrombosis.

Aims: Acenocoumarol, a commonly prescribed oral anticoagulant drug, exhibits wideinter-individual variability in response. This study aimed at evaluating the contribution of genetic variations in Vitamin K epoxide reductase complex, subunit 1 (VKORC1), to variability in the response to acenocoumarol, in patients with cerebral venous thrombosis (CVT). Place and Duration of Study: National Institute of Mental Health and Neuro Sciences, Bangalore, India, between September 2009 and January 2013. Methodology: 476 acenocoumarol-treated aseptic CVT patients (153 males, 323 females) were genotyped for VKORC1 -1639G>A and 1173C>T polymorphisms. Mean daily acenocoumarol dose for achieving and maintaining the optimum international normalized ratio (INR) was calculated for different genotypes. Results: Genotype distribution of VKORC1-1639G>A was as follows: 69.7% were wild,25.6% heterozygous and 4.6%, mutant. Mean acenocoumarol dose required to achieve the optimum INR was lower in heterozygous (1.82±0.71mg/day) and homozygous mutants (1.75±0.69mg/day) when compared to wild type patients (2.31±0.89mg/day). Bearing the VKORC1 -1639A allele independently increased the odds of requiring a low dose (Adjusted OR 3.9; 95% CI 1.97-7.73; p<0.0001). Significant differences in dose requirement during maintenance phase were observed in patients of different genotypes. VKORC1 -1639G>A and 1173C>T were observed to be tightly linked (r2=0.98) and no difference in the genotype distributions was observed between the two polymorphisms. Factors such as age and co-medication with phenytoin were also found to influence the drug dosage. Conclusion: Our findings support the use of VKORC1 genotyping during anticoagulation with acenocoumarol in patients with CVT.

Cytochrome P450 (CYP2C9*2,*3) & vitamin-K epoxide reductase complex (VKORC1 -1639G<A) gene polymorphisms & their effect on acenocoumarol dose in patients with mechanical heart valve replacement.

Background & objectives: Studies have demonstrated the effect of CYP2C9 (cytochrome P450) and VKORC1 (vitamin K epoxide reductase complex) gene polymorphisms on the dose of acenocoumarol. The data from India about these gene polymorphisms and their effects on acenocoumarol dose are scarce. The aim of this study was to determine the occurrence of CYP2C9*2,*3 and VKORC 1 -1639G>A gene polymorphisms and to study their effects on the dose of acenocoumarol required to maintain a target International Normalized Ratio (INR) in patients with mechanical heart valve replacement. Methods: Patients from the anticoagulation clinic of a tertiary care hospital in north India were studied. The anticoagulation profile, INR (International Normalized Ratio) values and administered acenocoumarol dose were obtained from the clinical records of patients. Determination of the CYP2C9*2,*3 and VKORC1 -1639G>A genotypes was done by PCR-RFLP (restriction fragment length polymorphism). Results: A total of 111 patients were studied. The genotype frequencies of CYP2C9 *1/*1,*1/*2,*1/*3 were as 0.883, 0.072, 0.036 and that of VKORC1 -1639G>A for GG, AG, and AA genotypes were 0.883, 0.090, and 0.027, respectively. The percentage of patients carrying any of the variant alleles of CYP2C9 and VKORC1 in heterozygous or homozygous form was 34% among those receiving a low dose of ≤20 mg/wk while it was 13.8 per cent in those receiving >20 mg/wk (P=0.014). A tendency of lower dose requirements was seen among carriers of the studied polymorphisms. There was considerable variability in the dose requirements of patients with and without variant alleles. Interpretation & conclusions: The study findings point towards the role of CYP2C9 and VKORC1 gene polymorphisms in determining the inter-individual dose variability of acenocoumarol in the Indian patients with mechanical heart valve replacement.

Pharmacogenetic typing for oral anti-coagulant response among factor V Leiden mutation carriers.

Context: Factor V Leiden mutation is the most common inherited predisposition for hypercoagulability and thereby a common genetic cause for initiation of oral anti-coagulation therapy. There is a dearth of knowledge of coumarin response profile in such thrombophilic population. Aims: The current pilot study aims to estimate coumarin sensitivity in an Indian cohort with an inherited thrombophilia risk factor (Factor V Leiden mutation carriers) based on the observed frequency of CYP2C9 *2, *3 and VKORC1-1639G >A genotype combinations. Settings and Design: A retrospective study carried out in a tertiary health care center in India. Materials and Methods: Carriers of FVL mutation were genotyped for CYP2C9 (*2, *3) and VKORC1 (-1639G >A) variants by PCR-RFLP technique. Statistical Analysis Used: Chi-square test to analyze difference in expected and observed genotype frequency. Results: Sixty-one (n = 61) unrelated carriers of FVL mutation were observed in the 13 years study period. The allele frequency of CYP2C9 *2, CYP2C9 *3, and VKORC1-1639A in this cohort was 0.06, 0.11, and 0.16, respectively. Six (9.7%) individuals had two of the three variant alleles (heterozygous or homozygous), and 28 (45.9%) were heterozygous for at least one polymorphism. Conclusions: Pre-prescription genotyping for coumarin drugs, if introduced in Indians with inherited thrombophilia (in whom oral anti-coagulant therapy may be necessary), is likely to identify 9.7% (hypersensitive) subjects in whom the optimum anti-coagulation may be achieved with reduced dosages, 44.3% (normal sensitivity) who may require higher dose and also 55.6% (hyper and moderate sensitivity) subjects who are likely to experience bleeding episodes.

Determinación del polimorfismo de CYP2C9*2 y su relación con la farmacocinética de acenocumarol en voluntarios sanos / Relation of cy2c9*2 polymorphism and acenocumarol pharmacokynetics in healthy volunteers

Antecedentes: La mayoría de los pacientes que reciben tratamientos con anticoagulantes orales por periodos prolongados presentan variabilidad en la respuesta. El acenocumarol es el anticoagulante oral más prescrito en nuestro país, es biotransformado principalmente por CYP2C9 e investigaciones recientes demuestran que la variante CYP2C9*2 es una de las responsables de la variabilidad de respuesta a acenocumarol. Objetivo: Determinar las diferencias en los parámetros farmacocinéticos de acenocumarol en voluntarios que presentan la variante alélica CYP2C9*2. Métodos: Se estudiaron 24 voluntarios sanos. La detección de genotipos se realizó mediante PCR-RFLP y los parámetros farmacocinéticos se obtuvieron mediante la concentración plasmática de acenocumarol usando un método validado para UPLC-MS/MS. Resultados: Del total de 24 voluntarios, 19 tenían el genotipo CYP2C9*1/*1 (wt/wt), 4 tenían genotipo CYP2C9*1/*2 (heterocigoto) y 1 voluntario tenía genotipo de CYP2C9*2/*2 (homocigoto recesivo). Los parámetros farmacocinéticos del acenocumarol no fueron significativamente diferentes entre los individuos con genotipo CYP2C9*2 y CYP2C9*1. Sin embargo, la farmacocinética de acenocumarol del individuo CYP2C9*2/*2 mostró diferencias relevantes con respecto a la observada en el grupo CYP2C9*1/*1 (tmáx aumentó 1,4 veces, ke disminuyó 1,8 veces y t1/2 aumentó 1,7 veces). Conclusión: La farmacocinética de acenocumarol en el individuo con el genotipo CYP2C9*2/*2 refleja una potencial relevancia de este polimorfismo en el tratamiento con acenocumarol.

Background: Most of the patients receiving anticoagulant therapy for extended periods show variability in their clinical response. Acenocumarol, the most commonly prescribed oral anticoagulant in our country, is biotransformed mainly through CYP2C9 and recent research shows that CYP2C9*2 variant is partly responsible for the variable response to ace-nocumarol. Aim: to determine pharmacokinetics parameters of acenocumarol in volunteers exhibiting the CYP2C9*2 polymorphic variant. Methods: Genotype detection was performed using PCR-RFLP and pharmacokinetics parameters were obtained from the acenocumarol concentrations, using a UPLC-MS/MS validated method. The project was approved by the institutional Ethics Committee of the University of Chile's Faculty of Medicine. Results: 19 out of 24 volunteers had the CYP2C9*1/*1 genotype, 4 the CYP2C9*1/*2 genotype (heterozygous) and 1 subject had the CYP2C9*2/*2 genotype (recessive homozygous). No statistically significant differences between acenocumarol pharmacokinetics parameters of CYP2C9*2 compared to those with normal variant, CYP2C9*1were observed.. However, a single individual with the CYP2C9*2/*2 genotype showed different phar-macokinetics parameters: tmáx and t1/2 were increased 1.4 and 1.7 times, respectively, and kc was 1.8 times lower compared to the group with the CYP2C9*1/*1 genotype. Conclusion: There are clear differences in genotype-dependent acenocoumarol pharmacokinetics in individuals with the CYP2C9*2/*2 genotype, reflecting a potential relevance of this polymorphism in anticoagulation with acenocumarol.