Estudio comparativo del uso de fármacos antiepilépticos durante el embarazo en un periodo de 12 años. Eficacia de los nuevos fármacos lamotrigina, levetiracetam y oxacarbamacepina / Comparative study of antiepileptic drug use during pregnancy over a period of 12 years in Spain. Efficacy of the newer antiepileptic drugs lamotrigine, levetiracetam, and oxcarbazepine

Introducción: El patrón de uso de fármacos antiepilépticos (FAE) durante el embarazo difiere entre países y está cambiando. Se desconoce en qué medida ello afecta a la población española. La eficacia de los nuevos fármacos en el control de las crisis es motivo de preocupación y puede haber cambiado a lo largo de los años debido a un mejor conocimiento de su uso durante el embarazo. Con el objetivo de analizar estos 2 aspectos reportamos los resultados del registro EURAP España durante un periodo de 12 años. Material y métodos: Tras el consentimiento informado, las pacientes son incluidas en el registro y evaluadas al inicio del embarazo, al final del segundo y tercer trimestres, después del parto y al año del nacimiento. Para los objetivos de este estudio hemos analizado: FAE, tipo de epilepsia, frecuencia de crisis por trimestres y a lo largo del embarazo, porcentaje de pacientes libres de crisis, y frecuencia de malformaciones congénitas mayores. Hemos comparado estas variables en 2 periodos (junio de 2001-octubre de 2007) y (enero de 2008-mayo de 2015). Resultados: Un total de 304 monoterapias del periodo antiguo se comparan con 127 del periodo nuevo. Observamos un ascenso del uso de levetiracetam (LEV) y un descenso del uso de carbamacepina (CBZ), fenitoína y fenobarbital; un leve descenso del uso de valproato (VPA), y un leve aumento de lamotrigina (LTG) y oxacarbamacepina (OXC). El tipo de epilepsia se mantiene estable para CBZ y VPA, pero cambia para LTG, con menos epilepsias generalizadas tratadas con este fármaco en el periodo nuevo. Ello no se asocia con un cambio significativo de la frecuencia de crisis, pero sí con un mejor control de las crisis de novo en el tercer trimestre. LEV se asocia a niveles de control de crisis similares a los de CBZ y VPA y mejor que con LTG. De las pacientes tratadas con LEV, un 64% tenían una epilepsia generalizada. Conclusiones: El patrón de uso de los diferentes FAE durante el embarazo está cambiando en España, con menos uso de CBZ, fenitoína y fenobarbital y un aumento del uso de LEV. El tipo de epilepsia también cambia, con un porcentaje inferior de pacientes tratadas con LTG para epilepsias generalizadas. LEV controla las crisis de manera similar a los fármacos clásicos y mejor que la LTG (AU)

Introduction: The prescription pattern of antiepileptic drugs (AEDs) during pregnancy is changing but to what extent this is occurring in Spain remains unknown. The efficacy of newer drugs for controlling seizures is a key issue and may have changed over the years as doctors gained familiarity with these drugs during pregnancy. To assess these 2 topics, we report the results from the Spanish EURAP register gathered over a 12-year period. Material and methods: After signing informed consent forms, patients were included in the register and evaluated at onset of pregnancy, at the end of the second and third trimesters, after delivery, and one year after delivery. For the purposes of this study, we analysed AEDs, type of epilepsy, seizure frequency per trimester and throughout pregnancy, percentage of seizure-free pregnancies, and frequency of congenital malformations. We then compared data from 2 periods (June 2001-October 2007) and (January 2008-May 2015). Results: We compared 304 monotherapies from the older period to 127 from the more recent one. There was a clear increase in the use of levetiracetam (LEV) with declining use of carbamazepine (CBZ), phenytoin, and phenobarbital; a slight decline in use of valproate (VPA), and a slight increase in the use of lamotrigine (LTG) and oxcarbazepine (OXC). Epilepsy types treated with CBZ and VPA remained unchanged, whereas fewer cases of generalised epilepsy were treated with LTG in the new period. This trend was not associated with significant changes in seizure frequency, but rather linked to better control over de novo seizures in the third trimester. LEV was similar to CBZ and VPA with regard to levels of seizure control, and more effective than LTG. Generalised epilepsy accounted for 64% of the cases treated with LEV. Conclusions: The prescription pattern of AEDs during pregnancy has changed in Spain, with diminishing use of CBZ, phenytoin, and phenobarbital. Changes also reflect the type of epilepsy, since there is less use of LTG for generalised epilepsy. LEV provides similar seizure control to that of the older AEDs, and it is more effective and better than LTG (AU)

Comparative study of antiepileptic drug use during pregnancy over a period of 12 years in Spain. Efficacy of the newer antiepileptic drugs lamotrigine, levetiracetam, and oxcarbazepine. / Estudio comparativo del uso de fármacos antiepilépticos durante el embarazo en un periodo de 12 años. Eficacia de los nuevos fármacos lamotrigina, levetiracetam y oxacarbamacepina.

INTRODUCTION: The prescription pattern of antiepileptic drugs (AEDs) during pregnancy is changing but to what extent this is occurring in Spain remains unknown. The efficacy of newer drugs for controlling seizures is a key issue and may have changed over the years as doctors gained familiarity with these drugs during pregnancy. To assess these 2 topics, we report the results from the Spanish EURAP register gathered over a 12-year period. MATERIAL AND METHODS: After signing informed consent forms, patients were included in the register and evaluated at onset of pregnancy, at the end of the second and third trimesters, after delivery, and one year after delivery. For the purposes of this study, we analysed AEDs, type of epilepsy, seizure frequency per trimester and throughout pregnancy, percentage of seizure-free pregnancies, and frequency of congenital malformations. We then compared data from 2 periods (June 2001-October 2007) and (January 2008-May 2015) RESULTS: We compared 304 monotherapies from the older period to 127 from the more recent one. There was a clear increase in the use of levetiracetam (LEV) with declining use of carbamazepine (CBZ), phenytoin, and phenobarbital; a slight decline in use of valproate (VPA), and a slight increase in the use of lamotrigine (LTG) and oxcarbazepine (OXC). Epilepsy types treated with CBZ and VPA remained unchanged, whereas fewer cases of generalised epilepsy were treated with LTG in the new period. This trend was not associated with significant changes in seizure frequency, but rather linked to better control over de novo seizures in the third trimester. LEV was similar to CBZ and VPA with regard to levels of seizure control, and more effective than LTG. Generalised epilepsy accounted for 64% of the cases treated with LEV. CONCLUSIONS: The prescription pattern of AEDs during pregnancy has changed in Spain, with diminishing use of CBZ, phenytoin, and phenobarbital. Changes also reflect the type of epilepsy, since there is less use of LTG for generalised epilepsy. LEV provides similar seizure control to that of the older AEDs, and it is more effective and better than LTG.

[Malformations and fetal death in the Spanish antiepileptic drug and pregnancy registry: results at 6 years]. / Malformaciones y muerte fetal en el registro español de fármacos antiepilépticos y embarazo: resultados a los 6 años.

INTRODUCTION: Pregnancy registries provide trustworthy information about the risks associated to antiepileptic drugs (AEDs). EURAP is a Prospective International Registry which include patients who takes AEDs at the time of conception. The data of the Spanish centers which are contributing to EURAP reflects the reality of our milieu. OBJECTIVES: To study the incidence of major congenital malformations (MCM) /and/or fetal-perinatal death (MFP) and determine his relationship to AEDs in the Spanish EURAP registry. METHODS: After informed consent, patients were included in the prospective Registry and evaluated: at the beginning, at the end of the second and third trimester, after delivery and one year after birth. A variety of variables were collected: demographic, type of epilepsy, frequency of seizures during pregnancy, AEDs and dose, potential toxics, folate use and dose, obstetric complications and information of the newborn. After 6 years of recruitment (June 2001-October 2007) we analyzed the results of this Registry in Spain with special attention on the incidence of major congenital malformations and foetal-perinatal death. RESULTS: Of a whole of 540 cases included in the Registry, 490 were prospective (included before the 16th week), of these we had complete information in 368 cases. Major congenital maLformations were present in 5% (n=13) of the child exposed to monotherapy and 12% (n=6) of those exposed to polytherapy (p=0.08). All polytherapy combinations with MCM, contained valproate. Of the variables analyzed only low weight at birth and the AEDs used showed statistically significant association with MCM and MFP. The percentage of MCM was superior for valproate, particularly at doses equal or superior of 1000 mg/day (16%), although differences were not statistically significant. The majority of ours patients were on monotherapy (83%) with AEDs at low doses and were taking 5 mg of folate. CONCLUSIONS: Patients on polytherapy, particularly those with valproate in combination present more risk of MCM. For monotherapy exposures only weight at birth and the AEDs used have association statistically significant with MC/MFP. Valproate in our series presents more risk than lamotrigine and does not show differences with regard to carbamazepine.

Malformaciones y muerte fetal en el registro español de fármacos antiepilépticos y embarazo: resultados a los 6 años / Malformations and fetal death in the Spanish antiepileptic drug and pregnancy registry: results at 6 years

Introducción. Los registros de embarazadas epilépticas proporcionan información fiable sobre los riesgos asociados al tratamiento antiepiléptico durante el embarazo. Con este fin se está realizado el registro EURAP, que es un estudio prospectivo observacional internacional que incluye mujeres tratadas con fármacos antiepilépticos (FAE) durante la concepción. Los datos de los centros españoles que participan en el registro reflejan cuál es la realidad en nuestro medio. Objetivos. Estudiar la incidencia de malformaciones congénitas (MCM) y/o muerte fetal perinatal (MFP), así como los posibles factores relacionados con las mismas en el registro EURAP España. Material y métodos. Tras el consentimiento informado las pacientes son incluidas en el registro prospectivo y son evaluadas en diferentes periodos: al inicio del embarazo, al final del segundo y tercer trimestre, después del parto y al año del nacimiento. Las variables que se analizan son: datos demográficos, tipo de epilepsia y frecuencia de crisis durante el embarazo, los FAE y dosis, otros tóxicos potenciales, uso de ácido fólico y dosis, complicaciones obstétricas y datos sobre el recién nacido. Tras 6 años de seguimiento (junio 2001- octubre 2007) se analizan los resultados de este registro en España, con especial énfasis en la incidencia de MCM y MFP. Resultados. De un total de 540 casos incluidos en el registro, son prospectivos (incluidos antes de la semana 16) 490 casos y disponemos de todos los datos para el análisis en 368. Presentaron MCM el 5% (n=13) de los neonatos expuestos a monoterapia y el 12% (n=6) de los expuestos a politerapia (p=0,08). Todas las politerapias asociadas a MCM incluían el ácido valproico. De las variables estudiadas sólo el bajo peso al nacer y el fármaco utilizado mostraron una asociación estadísticamente significativa con MCM y MFP. El porcentaje de MCM fue superior para el ácido valproico, particularmente a dosis igual o superior a 1.000 mg (16%), aunque las diferencias no fueron estadísticamente significativas. La mayoría de las pacientes estaban en monoterapia (83%) con dosis bajas de FAE y tomaban 5 mg de ácido fólico. Conclusiones. Los hijos de pacientes en politerapia, particularmente si incluyen el ácido valproico, son los que presentan más MCM. De los pacientes en monoterapia únicamente el peso al nacer y el FAE presentaban asociación significativa con MCM/MFP. En nuestra serie, el ácido valproico presenta más riesgo que la lamotrigina y no se observan diferencias respecto a carbamazepina (AU)

Introduction: Pregnancy registries provide trustworthy information about the risks associated to antiepileptic drugs (AEDs). EURAP is a Prospective International Registry which include patients who takes AEDs at the time of conception. The data of the Spanish centers which are contributing to EURAP reflects the reality of our milieu. Objectives: To study the incidence of major congenital malformations (MCM) /and/or fetal-perinatal death (MFP) and determine his relationship to AEDs in the Spanish EURAP registry. Methods: After informed consent, patients were included in the prospective Registry and evaluated: at the beginning, at the end of the second and third trimester, after delivery and one year after birth. A variety of variables were collected: demographic, type of epilepsy, frequency of seizures during pregnancy, AEDs and dose, potential toxics, folate use and dose, obstetric complications and information of the newborn. After 6 years of recruitment (June 2001-October 2007) we analyzed the results of this Registry in Spain with special attention on the incidence of major congenital malformations and foetal-perinatal death. Results: Of a whole of 540 cases included in the Registry, 490 were prospective (included before the 16th week), of these we had complete information in 368 cases. Major congenital maLformations were present in 5% (n=13) of the child exposed to monotherapy and 12% (n=6) of those exposed to polytherapy (p=0.08). All polytherapy combinations with MCM, contained valproate. Of the variables analyzed only low weight at birth and the AEDs used showed statistically significant association with MCM and MFP. The percentage of MCM was superior for valproate, particularly at doses equal or superior of 1000 mg/day (16%), although differences were not statistically significant. The majority of ours patients were on monotherapy (83%) with AEDs at low doses and were taking 5 mg of folate. Conclusions: Patients on polytherapy, particularly those with valproate in combination present more risk of MCM. For monotherapy exposures only weight at birth and the AEDs used have association statistically significant with MC/MFP. Valproate in our series presents more risk than lamotrigine and does not show differences with regard to carbamazepine (AU)

[Cost-minimisation analysis of the pharmacological treatment of epilepsy in Spain]. / Análisis de minimización de costes del tratamiento farmacológico antiepiléptico en España.

AIM: To use a model of economic evaluation to analyse the efficiency of therapy with the antiepileptic drugs indicated in recently diagnosed partial and generalised epilepsy. MATERIALS AND METHODS: The treatment of partial epilepsy and generalised epilepsy in Spain was taken as the basis to design two flexible simulation models of the decision tree type. The time horizon of the study was one year and the perspective was that of the Spanish National Health System, and indirect costs were also included. Clinical effectiveness data were obtained from a review of the literature on clinical trials. Information about resources was obtained from the opinions of a panel of experts. Unitary costs of resources were drawn from Spanish databases (euro 2003). The findings of the study were expressed in terms of average cost per patient with each therapeutic strategy, as well as the incremental cost of the different treatment strategies with respect to valproic acid. RESULTS: According to the literature that was reviewed, there are no differences in effectiveness from one antiepileptic drug to another. The incremental cost of the different therapeutic strategies, with respect to valproic acid, lies between 211 and 911 euros per patient and year in partial epilepsy, and between 1,355 and 1,297 euros per patient and year in the case of generalised epilepsy. CONCLUSIONS: The use of sustained-release valproic acid in recently diagnosed partial and generalised epilepsy would allow savings to be made in resources, with respect to the other antiepileptic drugs, and can therefore be considered to be the most effective therapeutic option.

Análisis de minimización de costes del tratamiento farmacológico antiepiléptico en España / Cost-minimisation analysis of the pharmacological treatment of epilepsy in spain

Objetivo. Analizar mediante un modelo de evaluación económica la eficiencia del tratamiento con los fármacos antiepilépticos indicados en la epilepsia parcial y generalizada de reciente diagnóstico. Materiales y métodos. Se diseñaron dos modelos de simulación flexible del tipo árbol de decisión, basados en el tratamiento de la epilepsia parcial y la epilepsia generalizada en España. El horizonte temporal del estudio fue de un año y la perspectiva fue la del Sistema Nacional de Salud, con inclusión también de los costes indirectos. Los datos de eficacia clínica se obtuvieron de una revisión de la bibliografía de ensayos clínicos. La información sobre uso de recursos se obtuvo de la opinión de un panel de expertos. Los costes unitarios de los recursos se extrajeron de bases de datos españolas (euro 2003). Los resultados del estudio se expresaron como coste medio por paciente con cada estrategia de tratamiento, y como coste incremental de las diferentes estrategias de tratamiento respecto al ácido valproico. Resultados. Según la bibliografía revisada, no existen diferencias en eficacia entre los fármacos antiepilépticos. El coste incremental de las diferentes estrategias de tratamiento respecto al ácido valproico se sitúa entre los 211 y 911 euros por paciente al año en epilepsia parcial, y entre 1.355 y 1.297 euros por paciente al año en epilepsia generalizada. Conclusión. La utilización de ácido valproico de liberación prolongada en la epilepsia parcial y generalizada de reciente diagnóstico supondría un ahorro de recursos respecto a los demás fármacos antiepilépticos; por tanto, puede considerarse la opción terapéutica más eficiente (AU)

Aim. To use a model of economic evaluation to analyse the efficiency of therapy with the antiepileptic drugs indicated in recently diagnosed partial and generalised epilepsy. Materials and methods. The treatment of partial epilepsy and generalised epilepsy in Spain was taken as the basis to design two flexible simulation models of the decision tree type. The time horizon of the study was one year and the perspective was that of the Spanish National Health System, and indirect costs were also included. Clinical effectiveness data were obtained from a review of the literature on clinical trials. Information about resources was obtained from the opinions of a panel of experts. Unitary costs of resources were drawn from Spanish databases (euro 2003). The findings of the study were expressed in terms of average cost per patient with each therapeutic strategy, as well as the incremental cost of the different treatment strategies with respect to valproic acid. Results. According to the literature that was reviewed, there are no differences in effectiveness from one antiepileptic drug to another. The incremental cost of the different therapeutic strategies, with respect to valproic acid, lies between 211 and 911 euros per patient and year in partial epilepsy, and between 1,355 and 1,297 euros per patient and year in the case of generalised epilepsy. Conclusions. The use of sustained-release valproic acid in recently diagnosed partial and generalised epilepsy would allow savings to be made in resources, with respect to the other antiepileptic drugs, and can therefore be considered to be the most effective therapeutic option (AU)