La Biblioteca Cochrane Plus - … · Las indicaciones oficiales de Canadá para la ciclosporina son el trasplante de órganos sólidos, el ... (e-CPS 2008). Muchas otras enfermedades

La Biblioteca Cochrane Plus 2011 Número 1 ISSN 1745-9990

EFECTO DE LA CICLOSPORINA SOBRE LA PRESIÓN ARTERIAL

Nadège Robert, Gavin WK Wong, James M Wright

Esta revisión debería citarse como: Nadège Robert, Gavin WK Wong, James M Wright. Efecto de la ciclosporina sobre la presión arterial (Revision Cochrane traducida). En: Biblioteca Cochrane Plus 2010

Número 1. Oxford: Update Software Ltd. Disponible en: http://www.update-software.com. (Traducida de The Cochrane Library, 2010 Issue 1 Art no. CD007893. Chichester, UK: John Wiley & Sons, Ltd.).

RESUMEN

Antecedentes

La ciclosporina es un agente inmunosupresor usado para tratar diferentes enfermedades autoinmunes. Las indicaciones oficiales de Canadá para la ciclosporina son el trasplante de órganos sólidos, el trasplante de médula ósea, la psoriasis, la artritis reumatoide y el síndrome nefrítico (e-CPS 2008)). Ya que el rango de indicaciones para el tratamiento con ciclosporina se encuentra en expansión, un mayor número de pacientes que reciben tratamiento crónico tendrán efectos secundarios posibles, la hipertensión es uno de los más comunes. Por lo tanto, es esencial conocer la magnitud del aumento de la presión arterial (PA) asociado con la ciclosporina para tratar apropiadamente a los pacientes que reciben el fármaco.

Objetivos

El objetivo primario de esta revisión sistemática es evaluar el efecto de la ciclosporina sobre la presión arterial, comparada con un placebo en ensayos aleatorios.

Estrategia de búsqueda

Se hicieron búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL) y en bases de datos bibliográficas, incluyendo MEDLINE (2000-2008) y EMBASE (1980-2008).

Criterios de selección

Se realizó la selección con los criterios de ensayos controlados aleatorios, a doble ciego que compararon la ciclosporina con un placebo. Se incluyó a todos los pacientes tratados con ciclosporina sin restricciones por tipo de enfermedad o por edad y sexo.

Obtención y análisis de los datos

Se aceptaban las mediciones de la presión arterial en cualquier contexto y por cualquier medio, incluido el método auscultatorio u oscilométrico, con una preferencia por la posición sentada. Los resultados de la presión arterial media se ingresaron como media del cambio del placebo y error estándar de la media (EEM). Si se proporcionaban los datos de la presión arterial en diferentes puntos temporales después del inicio del tratamiento con ciclosporina, se utilizaba la media del cambio de la PA ponderada en comparación con el placebo de todas las mediciones.

Resultados principales

La búsqueda identificó 1340 citas, de las cuales 17 cumplían los criterios de inclusión. Se crearon rangos de dosis de acuerdo a la administración de dosis habitualmente recomendada por el fabricante y se asignaron los 17 ensayos incluidos al rango de dosis correspondiente. Los resultados demuestran un gran aumento estadísticamente significativo de la presión arterial asociado con la ciclosporina. Parece haber un efecto relacionado con la dosis, con dosis inferiores (1-4 mg/kg/día) que aumenta la PA media en un promedio de 5 mmHg, y con dosis mayores (>10 mg/kg/día) que aumenta la PA media en un promedio de 11 mmHg. Además, en tres ensayos, el efecto parece ser similar después de una dosis única o el tratamiento crónico.

Conclusiones de los autores

La ciclosporina aumenta estadísticamente la presión arterial de forma significativa en comparación con el placebo, de una manera relacionada con la dosis. La magnitud del aumento de la presión arterial es clínicamente significativa y aumenta el riesgo de accidente cerebrovascular, infarto de miocardio, insuficiencia cardíaca y otros eventos cardiovasculares adversos asociados con una PA elevada. En consecuencia, los médicos que prescriben ciclosporina deben tratar de encontrar la dosis eficaz más baja para todos los pacientes que reciben este fármaco en forma crónica.

RESUMEN EN TÉRMINOS SENCILLOS

El tratamiento con ciclosporina aumenta la presión arterial

La ciclosporina es un agente inmunosupresor descubierto en 1972. Fue usado por primera vez para prevenir el rechazo después del trasplante de órganos y, más recientemente, para el tratamiento de las enfermedades autoinmunes. Los efectos secundarios comunes asociados al tratamiento con ciclosporina son la nefrotoxicidad y la hipertensión. Para observar la magnitud del aumento de la presión arterial a causa de la ciclosporina en comparación con un placebo, se realizaron búsquedas en la bibliografía científica disponible. Se identificaron 17 ensayos que cumplían con los criterios de inclusión de esta revisión y tenían datos extraíbles.

Esta revisión sistemática halló un aumento importante de la presión arterial para los pacientes tratados con ciclosporina, con una mejor estimación de la magnitud general de 7 mmHg. También se observó un efecto relacionado con la dosis, con un aumento promedio de la presión arterial media que variaba de 5 mmHg, con las dosis bajas, a 11 mmHg, con las dosis altas de ciclosporina. Este aumento es de importancia clínica e indica que los médicos que la prescriben deben tratar de encontrar la dosis eficaz más baja en todos los pacientes bajo tratamiento crónico.

ANTECEDENTES

Descripción de la condición

Es bien conocida la asociación entre la presión arterial elevada y el riesgo de eventos cardiovasculares. La hipertensión se describe como un efecto secundario muy común (≥ 10% cálculo de frecuencia) del tratamiento con ciclosporina (e-CPS 2008). Este efecto secundario es de interés para los médicos y los pacientes. Se han realizado dos ensayos para estudiar la efectividad de los fármacos antihipertensivos para la hipertensión asociada con la ciclosporina (Van den Dorpel 1994, Bursztyn 1997). Sin embargo, se desconoce la incidencia y la magnitud del aumento de la presión arterial en diferentes poblaciones de pacientes tratadas con ciclosporina.

Descripción de la intervención

La ciclosporina es un agente inmunosupresor que ya se había desarrollado en los años setenta. Su efecto está relacionado con la inhibición de la respuesta inmune dependiente de linfocitos T al interferir con la síntesis de la interleuquina-2 (Hess 1982, Elliott 1984). Se utilizó por primera vez para prevenir el rechazo en pacientes que habían recibido un trasplante. Las indicaciones de la ciclosporina se han expandido recientemente para incluir el tratamiento de enfermedades como la psoriasis, la artritis reumatoide, la esclerosis múltiple y la miastenia gravis. Los efectos secundarios comunes asociados al tratamiento con ciclosporina son la nefrotoxicidad y la hipertensión.

De qué manera podría funcionar la intervención

La expansión de las indicaciones del tratamiento con ciclosporina probablemente dará lugar a un número cada vez mayor de efectos secundarios. Las indicaciones oficiales de Canadá para la ciclosporina son el trasplante de órganos sólidos, el trasplante de médula ósea, la psoriasis, la artritis reumatoide y síndrome nefrítico (e-CPS 2008). Muchas otras enfermedades autoinmunes se están tratando con ciclosporina sin una indicación aprobada (Tugwell 1990 (3,8mg/kg/d).

No se conoce el mecanismo exacto por el cual aumenta la presión arterial con la ciclosporina, pero se han propuesto varias hipótesis. Algunos investigadores han sugerido que el aumento de la presión arterial con la ciclosporina es dependiente del sodio (Curtis 1988); dependiente del volumen (Porter 1990) o a causa de vasoconstricción directa (Xue 1987, Golub 1987).

Por qué es importante realizar esta revisión

Es esencial conocer la magnitud del aumento de la presión arterial asociado con la ciclosporina para tratar apropiadamente a los pacientes que reciben el fármaco. La variabilidad de la presión arterial medida en consultorios es amplia (Musini 2009), pero esta misma variabilidad hace difícil que los médicos puedan estar seguros si la ciclosporina aumenta la presión arterial en un paciente individual (en particular si el aumento se encuentra en el rango de 2-10 mmHg). Aunque el aumento de la presión arterial inducido por la ciclosporina es un efecto secundario reconocido, no se han documentado o cuantificado en una revisión sistemática la magnitud y las características de este efecto secundario.

OBJETIVOS

El objetivo primario de esta revisión sistemática es evaluar el efecto de la elevación de la presión arterial producida por la ciclosporina en comparación con un placebo en ensayos aleatorios. No se evalúan los eventos cardiovasculares adversos porque los ensayos son demasiado cortos.

MÉTODOS

Criterios para la valoración de los estudios para esta revisión

Tipos de estudios

El diseño del estudio debía cumplir con los siguientes criterios: Ensayos aleatorios doble ciego, controlados con placebo, de diseño paralelo o cruzado (cross over). Para evaluar una medida sumamente variable como la presión arterial, es esencial un diseño riguroso.

Duración de los estudios: mínimo un día.

Tipos de participantes

Todos los pacientes tratados con ciclosporina serán incluidos sin restricciones por tipo de enfermedad. También se incluirán participantes saludables que ingresan a los estudios en forma voluntaria. Tampoco hay restricciones de edad y sexo.

Tipos de intervenciones

Ciclosporina comparada con placebo.

Tipos de medida de resultado

Resultados primarios

El resultado primario es la media del cambio en la presión arterial media (PAM). Si se informan los datos de la presión arterial sistólica y diastólica (PAS/PAD), la PAM se calculará con la siguiente fórmula: PAM = PAD + 1/3 (PAS - PAD). Si sólo se informa la PAS o PAD, se usará la media del cambio en la presión informada.

Resultados secundarios

Media del cambio de la PA sistólica

Media del cambio de la PA diastólica

Media del cambio en la frecuencia cardíaca. Estos resultados secundarios quizá proporcionen alguna indicación en cuanto al mecanismo del cambio en la PA.

Media del cambio en la variabilidad de la presión arterial (desviación estándar).

Métodos de búsqueda para la identificación de los estudios

Búsquedas electrónicas

Se realizaron búsquedas de revisiones relacionadas en la Database of Abstracts of Reviews of Effectiveness (DARE).

Se realizaron búsquedas en las siguientes bases de datos electrónicas para localizar estudios primarios:

1. Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials, CENTRAL)

2. Bases de datos bibliográficas, incluyendo MEDLINE (2000-2008) y EMBASE (1980-2008)

Se realizaron búsquedas en MEDLINE mediante una estrategia que combinaba la Estrategia de Búsqueda Cochrane de Alta Sensibilidad para identificar ensayos aleatorios en MEDLINE: con la versión de máxima sensibilidad (revisión de 2008), con términos MeSH seleccionados y términos de texto libres relacionados con la ciclosporina. La estrategia de búsqueda para MEDLINE se trasladó a las otras bases de datos mediante el uso de vocabulario controlado apropiado según se considerara pertinente. No se utilizaron restricciones de idiomas. Las estrategias de búsqueda completas para MEDLINE se muestran en el Apéndice 1 ), EMBASE ( Apéndice 2 ) y CENTRAL ( Apéndice 3 ).

Búsqueda de otros recursos

Clinical Trials.gov y Current Controlled Trials

Listas de referencias de todos los documentos y revisiones pertinentes identificados incluidos y excluidos, como Faerber 2001

Se estableció contacto con los autores de los ensayos con datos incompletos para obtener la información faltante.

Se estableció contacto con los autores de los artículos pertinentes para solicitarles información con respecto a cualquier trabajo adicional publicado o no publicado

Obtención y análisis de los datos

Se aceptaron las mediciones de la presión arterial en cualquier contexto y por cualquier medio, incluido el método auscultatorio u oscilométrico. Si se informan las mediciones en más de una posición, la medición usada se elegía según la siguiente jerarquía: 1) sentando, 2) parado, 3) supino.

Los resultados de la presión arterial media se ingresaron como media del cambio del placebo y error estándar de la media (EEM). Si no se presentaba el error estándar de la media, se calculaba a partir de la DE del cambio, el intervalo de confianza del 95% (IC del 95%) o el valor de p. Si la DE, el EE o los IC del 95% no estaban disponibles, se imputaba la DE a partir de valores promedios, y se calculaba el EEM como DE imputada dividida por la raíz cuadrada de N.

Si se proporcionaban los datos de la presión arterial en diferentes puntos temporales después del inicio del tratamiento con ciclosporina, se utilizaba la media del cambio de la PA ponderada en comparación con el placebo de todas las mediciones.

Selección de los estudios

La selección de los estudios se basó en los criterios descritos anteriormente. Dos revisores independientes (NR y GW) evaluaron la elegibilidad de los ensayos y si hubo desacuerdo, se resolvió mediante un tercer revisor (JMW). Se tradujeron los estudios en idiomas distintos al inglés para determinar si podían ser incluidos. Para organizar las referencias, se usó el sistema informático Reference Manager 12.

Extracción y manejo de los datos

Dos revisores independientes (NR, GW) extrajeron los datos de forma independiente y los datos fueron verificados antes de introducirlos en el sistema informático Cochrane Review Manager, RevMan 5.

Si había desacuerdo, se resolvió mediante un tercer revisor (JMW).

Evaluación del riesgo de sesgo en los estudios incluidos

Se realizó la evaluación del riesgo de sesgo mediante el uso de las tablas de Riesgo de Sesgo para cada ensayo, según las normas Cochrane y los siguientes criterios:

1. Generación de secuencia

2. Ocultación de la asignación

3. Cegamiento o evaluación objetiva de los resultados primarios

4. Datos de resultado incompletos

5. Informe selectivo de las medidas de resultado

6. Otras fuentes de sesgo

Manejo de los datos faltantes

En el caso de que faltara la desviación estándar del cambio en la presión arterial, se imputó la desviación estándar según la información presente en el mismo ensayo o en otros ensayos que utilizaban el mismo fármaco. Se utilizó la siguiente jerarquía para imputar los valores de la desviación estándar:

1. desviación estándar del cambio en la presión arterial a partir de una posición diferente de la de los datos de la presión arterial

2. desviación estándar de la presión arterial al final del tratamiento

3. desviación estándar de la presión arterial al final del tratamiento, medida en una posición diferente de la de los datos de la presión arterial

4. Desviación estándar de la presión arterial inicial (excepto si esta medida se utilizó para los criterios de ingreso)

5. desviación estándar media del cambio en la presión arterial de otros ensayos que utilicen el mismo fármaco

Cuando fue necesario, se solicitaron los datos faltantes a los autores.

Evaluación de la heterogeneidad

Para identificar la heterogeneidad estadística, se utilizó la estadística I2 los valores >50% se

consideraron heterogéneos, y en ese caso, se usó el modelo de efectos aleatorios para evaluar la significación estadística del efecto del tratamiento.

Síntesis de los datos

Los datos de la presión arterial se sintetizaron en tablas y gráficos mediante RevMan 5.

Análisis de subgrupos e investigación de la heterogeneidad

Se realizaron análisis de subgrupos del efecto de diferentes dosis, diferentes estados de las enfermedades y duraciones del tratamiento sobre el efecto del tratamiento.

Análisis de sensibilidad

La solidez de los resultados se evaluó mediante las siguientes características:

1. Ensayos con datos de presión arterial medidos después del tratamiento con ciclosporina a corto plazo versus a largo plazo

2. Ensayos con diseño paralelo versus cruzado (cross over) de pacientes asignados al azar

3. Ensayos con datos de presión arterial medida en posición sentada versus otras posiciones

RESULTADOS

Descripción de los estudios

Ver: Características de los estudios incluidos; Características de los estudios excluidos.

La estrategia de búsqueda identificó 1340 citas, de las cuales 17 ensayos aleatorios controlados con placebo cumplieron con los criterios de inclusión y tuvieron datos extraíbles.

Uno de los estudios incluidos estaba publicado en alemán (Engst 1989 (5mg/kg/d). El resto estaba en inglés. Un total de 15 de los estudios incluidos fueron patrocinados por la industria. La tabla Características de los estudios incluidospresenta cada estudio detalladamente.

La ciclosporina se ha estudiado para muchas indicaciones diferentes, en varias dosis y durante duraciones variables. Lo que permitió analizar el efecto de la ciclosporina sobre la presión arterial de tres maneras diferentes.

Primero, se crearon tres rangos de dosis según la administración de la dosis habitualmente recomendada por el fabricante y CPS (e-CPS 2008) y se asignaron los 17 ensayos incluidos al rango de dosis correspondiente. Esta clasificación permite la observación de la respuesta a la dosis, pero no tiene en cuenta la duración del ensayo.

En segundo lugar, se separaron los ensayos sobre la base de si el fármaco era administrado como dosis única o dosis múltiples. Finalmente, se organizaron los ensayos según sus indicaciones.

El número de pacientes de los estudios incluidos era en general pequeño, a excepción de un ensayo que incluyó a 522 pacientes (Wolinsky 1990 (6mg/kg/d).

La tabla Características de los estudios excluidospresenta la razón por la cual los ensayos no fueron incluidos en esta revisión. La razón más común de la exclusión era la ausencia de informe de datos de la presión arterial utilizables.

Riesgo de sesgo en los estudios incluidos

Figura 1 resume la calidad metodológica de los estudios incluidos.

Ocho ensayos informaron una generación de la secuencia adecuada (Bendix 1996 (2,5mg/kg/d), De Lima 1998 (20mg/kd/d), Dougados 1988 (4,6mg/kg/d), Ellis 1986 14mg/kg/d, Ellis 1991, Reitamo 1993 (2,5mg/kg/d), Tugwell 1990 (3,8mg/kg/d),Wolinsky 1990 (6mg/kg/d). En sólo cuatro estudios se describió el método de ocultación de la asignación (De Lima 1998 (20mg/kd/d), Dougados 1988 (4,6mg/kg/d), Lock 1996 (5 mg/kg/d),Wolinsky 1990 (6mg/kg/d). Las otras publicaciones informaron sencillamente que el ensayo era "aleatorio", pero no aportaron detalles acerca del método de asignación al azar o del método de ocultación de la asignación.

En ocho estudios, se describió el método de cegamiento (Asberg 2000 (4mg/kg/d), De Lima 1998 (20mg/kd/d), Ellis 1991, Nizankowska 1995 (2,5mg), Reitamo 1993 (2,5mg/kg/d), Sowden 1991 (5mg/kg/d), Tugwell 1990 (3,8mg/kg/d),Wolinsky 1990 (6mg/kg/d). En el resto de los ensayos, se mencionó "doble ciego".

Ya que la presión arterial era el resultado primario de esta revisión y no era el resultado principal de los ensayos, fue frecuente el informe incompleto de la presión arterial y la desviación estándar. (ver Características de los estudios incluidos: , tablas de Riesgo de sesgo)

Muchos ensayos no informaron la presión arterial, posiblemente porque los valores supuestamente aumentaron. Este hecho se juzga como una causa potencial importante de sesgo en esta revisión.

Efectos de las intervenciones

La revisión demuestra un gran aumento estadísticamente significativo de la presión arterial asociado con la ciclosporina. La mejor estimación de la magnitud general es 7,4 mmHg con un rango de 2,5 mmHg a 16,4 mmHg. También parece haber un efecto relacionado con la dosis, con dosis inferiores aumenta la PA en 5 mmHg (IC del 95%: 2,8 a 7,2) y con dosis mayores aumenta la PA en 11 mmHg (IC del 95%: 7,2 a 15,6). En el subgrupo de dosis bajas, una estadística I

2 del 20% indicó un bajo grado de heterogeneidad entre los ensayos (P para

heterogeneidad = 0,28). En el subgrupo de dosis medias, los resultados fueron consistentes entre los diferentes estudios con una estadística I

2 del 0% y un valor de P para la

heterogeneidad de 0,85. La heterogeneidad entre los ensayos en el subgrupo de dosis altas

también fue baja, con una estadística I2 del 23% y un valor de P para la heterogeneidad de

0,25.

Además, aunque sólo hay tres ensayos, el efecto de la ciclosporina sobre la PA parece ser similar después de una dosis única y después de un tratamiento crónico. La duración promedio del tratamiento con dosis múltiples fue de 13,6 semanas (Ver Tabla 1). Ver Tabla 1

DISCUSIÓN

Resumen de los resultados principales

Primero, los ensayos incluidos fueron clasificados según la dosis de ciclosporina administrada, baja, media y alta. Los ensayos que utilizaban dosis múltiples de ciclosporina (tratamiento crónico) fueron separados de los ensayos que utilizaban una dosis única. Se consideró la diferencia media al final del tratamiento entre la ciclosporina y el placebo.

El aumento promedio de la PA media (7,4 mmHg) con la ciclosporina observado en esta revisión es clínicamente muy significativo. Es de una magnitud similar a la disminución promedio en la PA media de 6 mmHg observada con inhibidores de la enzima convertidora de la angiotensina y bloqueadores de los receptores de la angiotensina (Heran 2008a; Heran 2008b). Con un tratamiento crónico, un aumento de 7 mmHg de la PA media aumentaría significativamente el riesgo de accidente cerebrovascular, infarto de miocardio, insuficiencia cardíaca y otros eventos cardiovasculares adversos asociados con la PA elevada. Esta observación además es importante porque debido a la alta variabilidad de la PA con una desviación estándar de al menos 14/9 mmHg en la mayoría de los contextos clínicos sería difícil de detectar con certeza un aumento de la PA y la magnitud de tal aumento (Musini 2009). De hecho, para evaluar la magnitud del aumento de la PA de un paciente individual causada por la ciclosporina se requieren al menos 20 mediciones de la PA al valor inicial y otras 20 mediciones de la PA durante el tratamiento. En la mayoría de los contextos clínicos, este requerimiento no es posible o práctico y el monitoreo domiciliario de la PA sería la manera más eficaz de lograr la cantidad necesaria de datos de la PA.

Como segundo análisis, se clasificaron los ensayos incluidos según la indicación del tratamiento con ciclosporina para tratar de explorar el efecto de las diferentes duraciones de los ensayos y las diferencias de las poblaciones de los subgrupos (ver la Tabla 2). El número de ensayos en los diferentes subgrupos es inferior que en la comparación con los subgrupos de rangos de dosis. Pero en cada subgrupo que incluía dos o más ensayos, la diferencia de la PA media permanece con un aumento estadísticamente significativo en el grupo de ciclosporina comparado con el grupo de placebo. El aumento promedio de la PA media es también de 7 mmHg y es similar al primer análisis. Lo que indica que la duración de los ensayos no parece desempeñar una función importante en el aumento de la PA después de la administración de ciclosporina. Estos resultados indican que el efecto sobre la PA tiene probabilidad de ser clínicamente importante para todos los pacientes que reciben ciclosporina.__Ver Tabla 2

Compleción y aplicabilidad general de las pruebas

Al realizar esta revisión sistemática quedó claro que en la mayoría de los ensayos no se informó la PA. Este hecho es muy sorprendente ya que probablemente se haya registrado la PA dado que desde hace un tiempo se conoce que es posible que los pacientes que reciben ciclosporina experimenten un aumento en la PA. Es particularmente sorprendente que los ensayos con pacientes con trasplante renal no hayan informado la presión arterial. Esta falta de información indica que puede haber habido un sesgo por no informar deliberadamente sobre la PA cuando se elevó sustancialmente. De ser este el caso, el aumento clínicamente significativo de la PA documentado en esta revisión subestimaría el aumento real de la PA asociado con la ciclosporina.

Calidad de las pruebas

El número de pacientes en los ensayos incluidos era pequeño y varios ensayos no informaron el número de pacientes que se retiraron. No fue posible una evaluación minuciosa del riesgo de sesgo para cada ensayo porque faltaba mucha información. Sólo tres de 17 ensayos proporcionaron información sobre la ocultación de la asignación y ocho de 17 presentaron información sobre la generación de secuencias. En la mayoría de los ensayos, no fue posible

evaluar la calidad del doble ciego. Además, 15 de 17 ensayos informaron haber recibido apoyo del fabricante.

Se notó una gran variabilidad en los cambios de presión arterial. En cada subgrupo, el IC del 95% es amplio por lo que el IC del 95% del subgrupo de dosis bajas y del subgrupo de dosis medias se superponen, así como el IC del 95% del subgrupo de dosis medias y del subgrupo de dosis altas. Por lo tanto, sólo se tiene seguridad de que la dosis alta causó un aumento estadísticamente significativo en la presión arterial media mayor que la dosis baja. La alta variabilidad del efecto puede deberse al pequeño número de pacientes en los diferentes ensayos y por la alta variabilidad de la PA. En general, la información sobre el dispositivo usado para medir la PA así como la posición en la que se midió y el tiempo de la medición no estaba disponible. Cada uno de estos diferentes factores puede tener una influencia importante sobre la variabilidad de los resultados de la PA.

Sesgos potenciales en el proceso de revisión

Habría sido preferible informar por separado el aumento en la PA sistólica y diastólica. Sin embargo, ya que algunos de los ensayos sólo informaron la PA arterial media, para agrupar todos los ensayos, todos los datos se convirtieron a PA media. En un ensayo, sólo se informó la PA diastólica, en ese caso fue el valor usado. Sin embargo, es improbable que las conclusiones de esta revisión fueran diferentes si fuera posible informar el efecto sobre la PA sistólica y diastólica por separado.

Acuerdos y desacuerdos con otros estudios o revisiones

La búsqueda extensa y sistemática de esta revisión no identificó otras revisiones. Por lo tanto, se cree que este sería el primer intento en la bibliografía publicada por cuantificar el efecto de la ciclosporina sobre la PA.

CONCLUSIONES DE LOS AUTORES

Implicaciones para la práctica

Los profesionales de la salud que tratan pacientes con ciclosporina pueden esperar un aumento clínicamente significativo de la PA media de 5 mmHg con dosis bajas de ciclosporina (1-4 mg/kg/día) y de 11 mmHg con dosis altas de ciclosporina (>10 mg/kg/día). Por esta causa y otros posibles efectos tóxicos de la ciclosporina, los médicos que la prescriben deben tratar de encontrar la dosis eficaz más baja en todos los pacientes en tratamiento crónico. Para poder evaluar la magnitud del aumento de la PA de un paciente individual a causa de la ciclosporina, se requieren al menos 20 mediciones de la PA al valor inicial y otras 20 mediciones de la PA durante el tratamiento. El monitoreo domiciliario de la PA es la manera más eficaz para lograr la cantidad necesaria de datos de PA.

Implicaciones para la investigación

No hay excusas para no informar datos precisos de la PA sistólica y diastólica en todos los ensayos aleatorios sobre ciclosporina. Es responsabilidad de los autores y los editores asegurar que estos datos estén incluidos en el diseño de los ensayos y los informes. Se necesitan ECA que comparen la ciclosporina con otros inmunosupresores y que midan la mortalidad por todas las causas, la morbilidad grave por todas las causas (eventos adversos graves totales), así como la presión arterial y otros parámetros para evaluar el efecto neto de los diferentes tratamientos sobre la salud.

AGRADECIMIENTOS

Los revisores agradecen la ayuda proporcionada por el Grupo Cochrane de Hipertensión (Cochrane Hypertension Group).

DATOS Y ANÁLISIS

Comparación 1. PAM dosis múltiples

Título del subgrupo o resultado

Nº de estudios

Nº de participantes

Método estadístico Tamaño del efecto

1 Dosis baja (1-4 mg/kg/día)

6 Diferencia de medias (efectos fijos, IC del 95%)

4.99 [2.78, 7.20]

2 Dosis media (5-10 mg/kg/día)


6.43 [4.81, 8.06]

3 Dosis alta (> 10mg/kg/día)


11.37 [7.15, 15.60]

Comparación 2. PAM Dosis Única


Nº de estudios



1 Dosis baja (1-4 mg/kg/día)


3.0 [0.06, 5.94]

2 Dosis media (5-10 mg/kg/día)


10.9 [7.57, 14.23]

3 Dosis alta (> 10mg/kg/día)


4.0 [-2.87, 10.87]

Comparación 3. Indicación


Nº de estudios



1 Psoriasis 3 Diferencia de medias (efectos fijos, IC del 95%)

4.43 [0.37, 8.48]

2 Voluntarios saludables


9.95 [7.61, 12.29]

3 Artritis reumatoide 3 Diferencia de medias (efectos fijos, IC del 95%)

6.53 [3.47, 9.58]

4 Asma dependiente de corticosteroides


4.71 [0.41, 9.01]

5 Cirrosis biliar primaria


1.0 [-7.76, 9.76]

6 Pustulosis palmoplantar


0.8 [-4.92, 6.52]

7 Dermatitis atópica 1 Diferencia de medias (efectos fijos, IC del 95%)

6.8 [-0.57, 14.17]

8 Receptores de trasplantes renales


3.0 [0.06, 5.94]

9 Esclerosis múltiple 1 Diferencia de medias (efectos fijos, IC del 95%)

7.07 [5.05, 9.09]

APÉNDICES

Appendix 1. MEDLINE search strategy

Database: Ovid MEDLINE(R) <2000 to current>

1. Cyclosporine/

2. cyclosporine$.tw.

3. 1 or 2

4. randomized controlled trial.pt.

5. controlled clinical trial.pt.

6. randomized.ab.

7. placebo.ad.

8. drug therapy.fs.

9. randomly.ab.

10. trial.ab.

11. groups.ab.

12. or/4-11

13. animals/not (humans/ and animals/)

14. 12 not 13

15. 3 and 14

Appendix 2. EMBASE search strategy

1. random$.mp.

2. crossover$.mp.

3. cross over$.mp.

4. (doubl$ adj blind$).mp.

5. assign$.mp.

6. allocat$.mp.

7. Crossover Procedure/

8. Double Blind Procedure/

9. Randomized Controlled Trial/

10. or/1-9

11. cyclosporin$.mp. or cyclosporine/

12. placebo$.mp. or placebos/

13. 11 and 12

14. 10 and 13

Appendix 3. CENTRAL search strategy

1. cyclosporin$.mp. or Cyclosporine/

2. placebo$.mp. or Placebos/

3. 1 and 2

4. Double-Blind Method/ or double-blind.mp.

5. 4 and 3

ANTECEDENTES

Primera publicación del protocolo: Número 3, 2009 Primera publicación de la revisión: Número 1, 2010

CONTRIBUCIONES DE LOS AUTORES

Nadege Robert tuvo el rol principal en la búsqueda, la identificación y la evaluación de los estudios, la extracción y los análisis de los datos y la redacción de la revisión.

James Wright formuló la idea para el protocolo y desarrolló las bases para el protocolo con Nadege Robert y asistió con la interpretación de los datos y la redacción de la revisión.

Gavin Wong colaboró en el desarrollo de estrategias de búsqueda óptimas, la identificación de los ensayos, la evaluación de los estudios y la extracción de los datos.

DECLARACIONES DE INTERÉS

Ninguno declarado.

FUENTES DE FINANCIACIÓN

Recursos internos

University of BC, Canada.

Space, heat and light

Recursos externos

CIHR grant to Hypertension group, Canada.

Infrastructure support

INFORMACIÓN DE CONTACTO

Authors: Nadège Robert1, Gavin WK Wong

2, James M Wright

2

1University of Bern, Institut of Social and Preventive Medicine, Finkenhubelweg 11, Bern,

Switzerland 2University of British Columbia, Department of Anesthesiology, Pharmacology and

Therapeutics, 2176 Health Sciences Mall, Vancouver, Canada Contact: Nadège Robert

1 [email protected][email protected]. Editorial group:

Cochrane Hypertension Group (HM-HTN)

REFERENCIAS

( * indica la publicación principal del estudio)

REFERENCIAS DE LOS ESTUDIOS INCLUIDOS EN ESTA REVISIÓN

Asberg 2000 (4mg/kg/d) {published data only}

Asberg A, Berg KJ, Hartmann A. Each administration of cyclosporin A enhances skin microvascular reactivity in renal transplant recipients. Microvascular research 2000; 60(2): 81-

90.

Bendix 1996 (2.5mg/kg/d) {published data only}

Bendix G, Bjelle A. Adding low-dose cyclosporin A to parenteral gold therapy in rheumatoid arthritis: a double-blind placebo-controlled study. British journal of rheumatology 1996; 35(11):

1142-9.

De Lima 1998 (20mg/kd/d) {published data only}

De Lima JJ, Colombo FM, Lopes HF, Riccio GM, Krieger EM. Lack of effect of a single oral dose of cyclosporine on systemic blood pressure and on forearm blood flow and vascular resistance in humans. American Journal of Hypertension : Journal of the American Society of Hypertension 1998; 11(11 Pt 1): 1371-5.

Dougados 1988(4.6mg/kg/d) {published data only}

Dougados M, Awada H, Amor B. Cyclosporin in rheumatoid arthritis: a double blind, placebo controlled study in 52 patients. Annals of the Rheumatic Diseases 1988; 47(2): 127-33.

Ellis 1986 14mg/kg/d {published data only}

Ellis CN, David C. Gorsulowsky, Ted A. Hamilton, et al. Cyclosporine Improves Psoriasis in a Double-blind Study. JAMA 1986; 256(22): 3110-3116.

mailto:[email protected]



Ellis 1991 {published data only}

Ellis CN, Fradin Messana JM, Brown Siegel MT, Hartley AH, Rocher LL, Wheeler S, et al. Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial. The New England journal of medicine 1991; 324(5): 277-84.

Ellis 1991 5mg-7.5mg/kg/d {published data only}

Ellis 1991 A 3 mg/kg/d {published data only}

Engst 1989 (5mg/kg/d) {published data only}

Engst R. Results of cyclosporin treatment of severe, chronic psoriasis vulgaris. (German). Hautarzt 1989; 40(8): 486-9.

Hansen 1997 (10mg/kg/d) {published data only}

Hansen JM, FoghAndersen N, Christensen NJ, Strandgaard S. Cyclosporine-induced hypertension and decline in renal function in healthy volunteers. Journal of hypertension 1997; 15(3): 319-26.

Lock 1996 (5 mg/kg/d) {published data only}

Lock SH, Kay AB, Barnes NC. Double-blind, placebo-controlled study of cyclosporin A as a corticosteroid-sparing agent in corticosteroid-dependent asthma. American journal of respiratory and critical care medicine 1996; 153(2): 509-14.

Minuk1988(5.1-6.4mg/kg/d) {published data only}

Minuk GY, Bohme CE, Burgess E, Hershfield NB, Kelly JK, Shaffer EA, et al. Pilot study of cyclosporin A in patients with symptomatic primary biliary cirrhosis. Gastroenterology 1988; 95(5): 1356-63.

Nizankowska 1995 (2.5mg) {published data only}

Nizankowska E, Soja J, Pinis G, Bochenek G, Sladek K, Domagala B, et al. Treatment of steroid-dependent bronchial asthma with cyclosporin. The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology 1995; 8(7): 1091-9.

Reitamo 1993 (2.5mg/kg/d) {published data only}

Reitamo S, Erkko P, Remitz A, Lauerma AI, Montonen O, Harjula K. Cyclosporine in the treatment of palmoplantar pustulosis. A randomized, double-blind, placebo-controlled study. Archives of Dermatology 1993; 129(10): 1273-9.

Sowden 1991 (5mg/kg/d) {published data only}

Sowden JM, BerthJones J, Ross JS, Motley RJ, Marks R, Finlay AY, et al. Double-blind, controlled, crossover study of cyclosporin in adults with severe refractory atopic dermatitis. Lancet 1991; 338(8760): 137-40.

Sturrock 1994 (15-20mg) {published data only}

Sturrock NDC, Lang CC, Baylis PH, Struthers AD. Sequential effects of cyclosporine therapy on blood pressure, renal function and neurohormones. Kidney international 1994; 45(4): 1203-10.

Sturrock 1995 (10mg/kg/d) {published data only}

Sturrock NDC, Lang CC, MacFarlane LJ, Dockrell MEC, Ryan M, Webb DJ, et al. Serial changes in blood pressure, renal function, endothelin and lipoprotein (a) during the first 9 days of cyclosporin therapy in males. Journal of hypertension 1995; 13(6): 667-73.

Tugwell 1990 (3.8mg/kg/d) {published data only}

Tugwell P, Bombardier C, Gent M, Bennett KJ, Bensen WG, Carette S, et al. Low-dose cyclosporin versus placebo in patients with rheumatoid arthritis. Lancet 1990; 335(8697): 1051-5.

Wolinsky 1990 (6mg/kg/d) {published data only}

Wolinsky JS, Scheinberg LC, Smith CR, Giesser BS, Traugott U, Aisen M, et al. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: A randomized, double-blinded, placebo-controlled clinical trial. Annals of Neurology 1990; 27(6): 591-605.

REFERENCIAS DE LOS ESTUDIOS EXCLUIDOS DE ESTA REVISIÓN

Appel 1988 {published data only}

Appel SH, Stewart SS, Appel V, Harati Y, Mietlowski W, Weiss W, et al. A double-blind study of the effectiveness of cyclosporine in amyotrophic lateral sclerosis. Archives of Neurology 1988; 45(4): 381-6.

Barenbrock 1995 {published data only}

Barenbrock M, Colmorgen U, Firschka E, Gellert J, Lippert J, Schroder K, et al. A multicenter, randomized, double-blind, placebo-controlled, two-year trial to study the effect of nitrendipine on chronic renal transplant function. Clinical nephrology 1995; 43(6): 388-91.

Berg 1991 {published data only}

Berg KJ, Holdaas H, Endresen L, Fauchald P, Hartmann A, Pran T, et al. Effects of isradipine on renal function in cyclosporin-treated renal transplanted patients. Nephrology Dialysis Transplantation 1991; 6(10): 725-30.

Binet 2000 {published data only}

Binet I, Wallnofer A, Weber C, Jones R, Thiel G. Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A. Kidney international 2000; 57(1): 224-31.

Brynskov 1990 {published data only}

Brynskov J, Tvede N. Plasma interleukin-2 and a soluble/shed interleukin-2 receptor in serum of patients with Crohn's disease. Effect of cyclosporin. Gut 1990; 31(7): 795-9.

Bursztyn 1997 {published data only}

Bursztyn M, Zelig O, Or R, Nagler A. Isradipine for the prevention of cyclosporine-induced hpertension in allogeneic bone marrow transplant recipients: a randomized, double-blind study. Transplantation 1997; 63(7): 1034-6.

Calabrese 2002 {published data only}

Calabrese LH, Lederman MM, Spritzler J, Coombs RW, Fox L, Schock B, et al. Placebo-controlled trial of cyclosporin-A in HIV-1 disease: implications for solid organ transplantation. Journal of acquired immune deficiency syndromes (1999) 2002; 29(4): 356-62.

Camp 1993 {published data only}

Camp RD, Reitamo S, Friedmann PS, Ho V, Heule F. Cyclosporin A in severe, therapy-resistant atopic dermatitis: report of an international workshop, April 1993. British Journal of Dermatology 1993; 129(2): 217-20.

Cattran 1995 {published data only}

Cattran DC, Greenwood C, Ritchie S, Bernstein K, Churchill DN, Clark WF, et al. A controlled trial of cyclosporine in patients with progressive membranous nephropathy. Canadian Glomerulonephritis Study Group. Kidney international 1995; 47(4): 1130-5.

Dalavanga 1987 {published data only}

Dalavanga YA, Detrick B, Hooks JJ, Drosos AA, Moutsopoulos HM. Effect of cyclosporin A (CyA) on the immunopathological lesion of the labial minor salivary glands from patients with Sjogren's syndrome. Annals of the Rheumatic Diseases 1987; 46(2): 89-92.

de Vries 1990 {published data only}

de Vries J, Baarsma GS, Zaal MJ, BoenTan TN, Rothova A, Buitenhuis HJ, et al. Cyclosporin in the treatment of severe chronic idiopathic uveitis. The British journal of ophthalmology 1990; 74(6): 344-9.

Dijkmans 1987 {published data only}

Dijkmans van Rijthoven AW, Goei The HS, MontnorBeckers ZL, Jacobs PC, Cats A. Effect of cyclosporin on serum creatinine in patients with rheumatoid arthritis. European journal of clinical pharmacology 1987; 31(5): 541-5.

Drosos 1986 {published data only}

Drosos AA, Skopouli FN, Costopoulos JS, Papadimitriou CS, Moutsopoulos HM. Cyclosporin A (CyA) in primary Sjogren's syndrome: a double blind study. Annals of the Rheumatic Diseases 1986; 45(9): 732-5.

Erkko 1998 {published data only}

Erkko P, Granlund H, Remitz A, Rosen K, Mobacken H, Lindelof B, et al. Double-blind placebo-controlled study of long-term low-dose cyclosporin in the treatment of palmoplantar pustulosis. The British journal of dermatology 1998; 139(6): 997-1004.

Feagan 1994 {published data only}

Feagan BG, McDonald JWD, Rochon J, Laupacis A, Fedorak RN, Kinnear D, et al. Low-dose cyclosporine for the treatment of Crohn's disease. New England Journal of Medicine 1994; 330(26): 1846-51.

Feutren 1990 {published data only}

Feutren G, Abeywickrama K, Friend D, von Graffenried B. Renal function and blood pressure in psoriatic patients treated with cyclosporin A. The British journal of dermatology 1990; 122 Suppl 36: 57-69.

Gerards 2003 {published data only}

Gerards AH Landewe RBM Prins APA Bruijn GAW Goei The HS Laan. Erratum: Cyclosporin A monotherapy versus cyclosporin A and methotrexate combination therapy in patients with early rheumatoid arthritis: A double blind randomised placebo controlled trial (Annals of the Rheumatic Diseases (2003) 62 (291-296)). Annals of the Rheumatic Diseases 2003; 62(11):

291-6.

Grattan 2000 {published data only}

Grattan CE, O'Donnell BF, Francis DM, Niimi N, Barlow RJ, Seed PT, et al. Randomized double-blind study of cyclosporin in chronic 'idiopathic' urticaria. The British journal of dermatology 2000; 143(2): 365-72.

Gupta 1991 {published data only}

Gupta AK, Rocher LL, Schmaltz SP, Goldfarb MT, Brown Ellis CN, Voorhees JJ. Short-term changes in renal function, blood pressure, and electrolyte levels in patients receiving cyclosporine for dermatologic disorders. Archives of Internal Medicine 1991; 151(2): 356-62.

Kuypers 2004 {published data only}

Kuypers DRJ, Neumayer HH, Fritsche L, Budde K, Rodicio JL, Vanrenterghem Y. Calcium channel blockade and preservation of renal graft function in cyclosporine-treated recipients: A prospective randomized placebo-controlled 2-year study. Transplantation 2004; 78(8): 1204-11.

Lai 1987 {published data only}

Lai KN, Lai FM, Li PK, Vallance-Owen J. Cyclosporin treatment of IgA nephropathy: a short term controlled trial. British Medical Journal Clinical Research Ed 1987; 295(6607): 1165-8.

Lai 1991 {published data only}

Lai KN, Lam CW, Cheng IK, Tam JS, Lai FM. Effect of cyclosporine A on circulating immune complexes in IgA nephropathy. International Urology & Nephrology 1991; 23(3): 265-74.

Leenen 2007 {published data only}

Leenen FH, Coletta E, Davies RA. Prevention of renal dysfunction and hypertension by amlodipine after heart transplant. The American Journal of Cardiology 2007; 100(3): 531-5.

Lieberman 1996 {published data only}

Lieberman KV, Tejani A. A randomized double-blind placebo-controlled trial of cyclosporine in steroid-resistant idiopathic focal segmental glomerulosclerosis in children. Journal of the American Society of Nephrology : JASN 1996; 7(1): 56-63.

Lombard 1993 {published data only}

Lombard M, Portmann B, Neuberger J, Williams R, Tygstrup N, Ranek L, et al. Cyclosporin A treatment in primary biliary cirrhosis: results of a long-term placebo controlled trial. Gastroenterology 1993; 104(2): 519-26.

Madsen 1995 {published data only}

Madsen JK, Kornerup HJ, Pedersen EB. Effect of felodipine on renal haemodynamics and tubular sodium handling after single-dose cyclosporin infusion in renal transplant recipients treated with azathioprine and prednisolone. Scandinavian journal of clinical and laboratory investigation 1995; 55(7): 625-33.

Madsen 1996 {published data only}

Madsen JK, Jensen JD, Jensen LW, Pedersen EB. Pharmacokinetic interaction between cyclosporine and the dihydropyridine calcium antagonist felodipine. European journal of clinical pharmacology 1996; 50(3): 203-8.

Martin 1991 {published data only}

Martin S, Schernthaner G, Nerup J, Gries FA, Koivisto VA, Dupre J, et al. Follow-up of cyclosporin A treatment in type 1 (insulin-dependent) diabetes mellitus: lack of long-term effects. Diabetologia 1991; 34(6): 429-34.

Mazzeo 2008 {published data only}

Mazzeo AT, Alves OL, Gilman CB, Hayes RL, Tolias C, Niki Kunene K, et al. Brain metabolic and hemodynamic effects of cyclosporin A after human severe traumatic brain injury: A microdialysis study. Acta Neurochirurgica 2008; 150(10): 1019-31.

Meffert 1997 {published data only}

Meffert H, Brautigam M, Farber L, Weidinger G. Low-dose (1.25 mg/kg) cyclosporin A: treatment of psoriasis and investigation of the influence on lipid profile. Acta Dermato-Venereologica 1997; 77(2): 137-41.

Miranda 2004 {published data only}

Miranda JM, AlvarezNemegyei J, Saavedra Teran L, GalvanVillegas F, GarciaFigueroa J, Jara LJ, et al. A randomized, double-blind, multicenter, controlled clinical trial of cyclosporine plus chloroquine vs. cyclosporine plus placebo in early-onset rheumatoid arthritis. Archives of Medical Research 2004; 35(1): 36-42.

Munro 1994 {published data only}

Munro CS, Levell NJ, Shuster S, Friedmann PS. Maintenance treatment with cyclosporin in atopic eczema. The British journal of dermatology 1994; 130(3): 376-80.

Papp 2008 {published data only}

Papp K, Bissonnette R, Rosoph L, Wasel N, Lynde CW, Searles G, et al. Efficacy of ISA247 in plaque psoriasis: a randomised, multicentre, double-blind, placebo-controlled phase III study. Lancet 2008; 371(9621): 1337-42.

Parrott 2005 {published data only}

Parrott NR, Hammad AQ, Watson CJ, Lodge JP, Andrews CD. Multicenter, randomized study of the effectiveness of basiliximab in avoiding addition of steroids to cyclosporine a monotherapy in renal transplant recipients. Transplantation 2005; 79(3): 344-8.

Rudge 1989 {published data only}

Rudge P, Koetsier JC, Mertin J, Mispelblom Beyer JO, Van Walbeek HK, Clifford Jones R, et al. Randomised double blind controlled trial of cyclosporin in multiple sclerosis. Journal of neurology, neurosurgery, and psychiatry 1989; 52(5): 559-65.

Salek 1993 {published data only}

Salek Finlay AY, Luscombe DK, Allen BR, BerthJones J, Camp RD, GrahamBrown RA, et al. Cyclosporin greatly improves the quality of life of adults with severe atopic dermatitis. A randomized, double-blind, placebo-controlled trial. The British journal of dermatology 1993; 129(4): 422-30.

Sandborn 1993 {published data only}

Sandborn WJ, Wiesner RH, Tremaine WJ, Larusso NF. Ulcerative colitis disease activity following treatment of associated primary sclerosing cholangitis with cyclosporin. Gut 1993; 34(2): 242-6.

Sihra 1997 {published data only}

Sihra Kon OM, Durham SR, Walker S, Barnes NC, Kay AB. Effect of cyclosporin A on the allergen-induced late asthmatic reaction. Thorax 1997; 52(5): 447-52.

Stange 1995 {published data only}

Stange EF, Modigliani R, Pena AS, Wood AJ, Feutren G, Smith PR. European trial of cyclosporine in chronic active Crohn's disease: a 12-month study. The European Study Group. Gastroenterology 1995; 109(3): 774-82.

van Joost 1988 {published data only}

van Joost T, Bos JD, Heule F, Meinardi MM. Low-dose cyclosporin A in severe psoriasis. A double-blind study. The British journal of dermatology 1988; 118(2): 183-90.

van Joost 1994 {published data only}

van Joost T, Heule F, Korstanje M, van den Broek MJ, Stenveld HJ, van Vloten WA. Cyclosporin in atopic dermatitis: a multicentre placebo-controlled study. The British journal of dermatology 1994; 130(5): 634-40.

Van Rijthoven 1986 {published data only}

Van Rijthoven AWAM, Dijkmans BAC, Goei The HS. Cyclosporin treatment for rheumatoid arthritis: A placebo controlled, double blind, multicentre study. Annals of the Rheumatic Diseases 1986; 45(9): 726-31.

Vena 2006 {published data only}

Vena GA, Cassano N, Colombo D, Peruzzi E, Pigatto P, NeoI Study Group. Cyclosporine in chronic idiopathic urticaria: a double-blind, randomized, placebo-controlled trial. Journal of the American Academy of Dermatology 2006; 55(4): 705-9.

Wiesner 1990 {published data only}

Wiesner RH, Ludwig J, Lindor KD, Jorgensen RA, Baldus WP, Homburger HA, et al. A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis. New England Journal of Medicine 1990; 322(20): 1419-24.

REFERENCIAS ADICIONALES

Bursztyn 1997

Bursztyn M. Zelig O. Or R. Nagler A. Isradipine for the prevention of cyclosporine-induced hypertension in allogeneic bone marrow transplant recipients: a randomized, double-blind study. Transplantation 1997 Apr 15; 63(7): 1034-6.

Curtis 1988

Curtis JJ. Luke RG. Jones P. Diethelm AG. Hypertension in cyclosporine-treated renal transplant recipients is sodium dependent. American Journal of Medicine 1988 Aug; 85(2): 134-8.

e-CPS 2008

Canadian Pharmacists Association. Compendium of Pharmaceuticals and Specialties. . Vol. online version, Ottawa, Ontario, Canada: Canadian Pharmacists Association, 2008.

Elliott 1984

Elliott JF, Lin Y, Mizel SB, Bleackley RC, Harnish DG, Paetkau V. Induction of interleukin 2 messenger RNA inhibited by cyclosporine A. Science 1984; 226: 1439-41.

Faerber 2001

Faerber L, Braeutigam M, Weidinger G, Mrowietz U, Christophers E, Schulze HJ, et al. Cyclosporine in severe psoriasis. Results of a meta-analysis in 579 patients. American Journal of Clinical Dermatology 2001; 2(1): 41-7.

Golub 1987

Golub MS, Beger ME. Direct augmentation by cyclosporine A of vascular contractile response to nerve stimulation. Hypertension 1987; 9 (suppl 3): 96-100.

Heran 2008a

Heran BS, Wong MMY, Heran IK, Wright JM. Blood pressure lowering efficacy of angiotensin converting enzyme (ACE) inhibitors for primary hypertension. Cochrane Database of Systematic Reviews 2008, Issue 4. [DOI: 10.1002/14651858.CD003823.pub2.]

Heran 2008b

Heran BS, Wong MMY, Heran IK, Wright JM. Blood pressure lowering efficacy of angiotensin receptor blockers for primary hypertension. Cochrane Database of Systematic Reviews 2008, Issue 4. [DOI: 10.1002/14651858.CD003822.pub2]

Hess 1982

Hess AD, Tutschka PJ, Santos GW. Effect of cyclosporine A on human lymphocyte response in vitro. III. CyA inhibits the production of T lymphocyte growth factors in secondary mixed-lymphocyte responses but does not inhibit the response of primed lymphocytes to TCGF. Immunol 1982; 128: 355-9.

Musini 2009

Musini VM, Wright JM. Factors affecting blood pressure variability: lessons learned from two systematic reviews of randomized controlled trials. PLoS One 2009; 4(5): e5673. [PUBMED: 19479061]

Porter 1990

Porter GA, Bennett WM, Sheps SG. Cyclosporine-associated hypertension. National High Blood Pressure Education Program. Archives of internal medicine 1990 (Feb); 150(2): 280-3.

Van den Dorpel 1994

Van den Dorpel MA. Zietse R. Ijzermans JN. Schalekamp MA. Weimar W. Effect of isradipine on cyclosporin A-related hypertension. Blood Pressure Supplement 1994; 1: 50-3.

Xue 1987

Xue H, Bukowski R, McCarron DA, Bennett WM. Cyclosporine A induces constriction in isolated rat aorta. Transplantation 1987; 43: 715-718.

TABLAS

CARACTERÍSTICAS DE LOS ESTUDIOS

Características de los estudios incluidos [ordenados por ID del estudio]

Asberg 2000 (4mg/kg/d)

Methods RCT, double-blind, placebo controlled, cross-over arm (with a 7 day wash out period between the two investigations), one day trial, blood pressure measurement every 20 minutes for 3,5-h after intake of cyclosporine or placebo.

Participants 14 renal transplant recipients (4 females) all with stable renal function; median age 48 years (range 24-63 years); investigation 4-12 weeks (median 6 weeks) following transplantation

Interventions Individualized full 24-h doses of cyclosporine were given either as oral cyclosporine or as matching placebo on the investigation

http://dx.doi.org/10.1002/14651858.CD003823.pub2.

http://dx.doi.org/10.1002/14651858.CD003822.pub2

days. The same individualized doses was used on both investigation days median 4.1 mg/kg (range 2.0-8.5 mg/kg).

Outcomes ACh responses; reactive Hyperemia; Mean arterial blood pressure. Blood pressure was monitored with a semi-automatic sphygmomanometer ( BOSO Bosotron 2, Bosh Sohn, Jungingen, Germany).

Notes Single dose of cyclosporine was investigated. MAP was measured.

Risk of bias

Item Authors' judgement

Description

Adequate sequence generation?

Unclear No information on sequence generation

Allocation concealment?

Unclear No information on allocation concealment

Blinding? All outcomes

Yes Patients received the opposite drug later in the morning to ascertain a double-blinded design.

Incomplete outcome data addressed? All outcomes

Unclear The report of BP result was incomplete

Free of selective reporting?

Yes All outcomes are reported

Free of other bias?

Unclear Manufacturer sponsored

Bendix 1996 (2.5mg/kg/d)

Methods RCT, double-blind, placebo controlled, parallel arm; inclusion of 40 out-patients at the Department of Rheumatology, Sahlgrenska University Hospital, Gothenburg; patients were sequentially allocated to the two treatments by a computer program based on nine pre-selected variables, 6 months trial

Participants Patients with rheumatoid arthritis aged between 18 and 70 years with disease onset after age 16.

Patients with hypertension ( diastolic >90mmHg or systolic >160mmHg) were excluded

19 patients were randomised to treatment with PGT and CsA and 21 to PGT and placebo. 36 patients completed the 6 months

therapy.

Interventions Investigation of oral cyclosporine versus placebo effect added to a parenteral gold therapy (PGT).

The final mean dose of cyclosporine was 2.89 ± 0.69 mg/Kg/d (range 1.70-3.75). Monthly individualized adaptation of the dose was made by an unblinded physician.

Outcomes Morning stiffness, Ritchie Articular Index, number of tender and swollen joints,

SBP and DBP measurements were included in tolerability tests

Notes

Risk of bias


Description


Yes "The patients were sequentially allocated to the two treatments by a computer program based on nine pre-selected variables: age, sex, duration of RA, morning stiffness, ESR, pain at rest, number of ARA remission criteria fulfilled, rheumatoid factor titre ≥ 1/80 (45) and the amount of previous gold."




Unclear "At month 2, 4 and 6 patients visited the blinded examiner for recording of data. Also each month patients met the unblinded clinician at the same time of the day for clinical examination, laboratory test and adjustment of therapy due to adverse events."


Unclear SBP/DBP and standard deviation were reported. MAP had to be calculated.



Free of other bias?

Unclear Manufacturer supported

De Lima 1998 (20mg/kd/d)

Methods RCT, double-blind, placebo controlled, cross-over arm with 2 weeks wash-out period between the two intervention days; single

dose

Participants 16 healthy adults from 21 to 61 years old (mean 37.6 ± 12.4); 10 men and 6 women; 14 whites, one black and one oriental; mean body weight 64.2±10.2 kg (range 48.0 to 80.0)

Interventions Cyclsoporine oral solution or a vehicle solution

All measurements were conducted in the morning between 9:00 and 10:00 AM after a resting period of 30 to 40 min and repeated 2h after drug administration.

Systolic and diastolic blood pressure were continuously determined in the supine position with Finapres apparatus attached to the left third finger and recorded on a multichannel polygraph. BP was also measured on the brachial artery by the auscultatory method determined at the initiation of each experimental period in 10 selected individuals.

Outcomes Evalute the effect of a single oral dose of cyclosporine on mean blood pressure (MBP), heart rate (HR), forearm blood flow (FBF), and vascular resistance (FVR)

Notes

Risk of bias


Description


Yes "The order of the drug administration was randomly determined by a computer-generated list that was known only to a registered nurse who was also appointed to prepare the milk-cyclosporine or olive oil blend."


Yes "Subjects and investigators were unaware of the sequence of drug administration up to the conclusion of the data analysis. The tracings were analysed by two investigators in a blind manner."


Yes "Cyclosporine solution and olive oil were blended with 200ml milk before administration."


Yes SBP/DBP, MAP and standard deviation were reported.



Free of other bias?

Yes Not manufacturer sponsored, all outcomes are well reported.

Dougados 1988(4.6mg/kg/d)

Methods RCT, double-blind, placebo controlled, parallel arm; 4 months study; CyA and placebo were supplied in coded, unidentifiable, liquid solution for oral administration.

Participants 52 patients with rheumatoid arthritis; 4 withdrawn in the CyA group because of side effects and 2 in the placebo group because of inefficacy.

Interventions Oral administration of the study drug twice daily. CyA dose after 4 months therapy was 4.6mg/kg/d

Outcomes Efficacy of CyA in rheumatoid arthritis according to following clinical assessments: severity of pain evaluated by a visual analogue scale and by Ritchie index, morning stiffness, swollen joints, grip strength and Lee functional index.

SBP and DBP measurements were included in the assessment of acceptability of treatment.

Notes

Risk of bias


Description


Yes "Patients were supplied in coded, unidentifiable, liquid solution for oral administration. The study drug was supplied according to a randomisation scheme."


Yes "At the start of the study both investigators were unaware of the meaning of the randomisation code. The investigator who evaluated the efficacy parameters remained unaware of the code meaning until the last patient had completed the study."


Unclear No information on blinding


No Standard deviation of BP results had to be imputed and MAP calculated

"6/52 patients withdrew: 2 in placebo group because of inefficacy and 4 in CsA group because of side effects. These 6 patients were considered therapeutic failures."



Free of other bias?

Unclear Manufacter sponsored

Ellis 1986 14mg/kg/d

Methods RCT, double-blind, placebo controlled, parallel arm, one month study

Participants 21 patients with severe plaque psoriasis at least 18 years old

Patients were assigned to one of two groups by use of a table of random numbers. 11 in CyA group and 10 in placebo group.

Interventions Adminitration of either 14mg/kg/d cyclosporine in a vehicle consisting of olive oil and polyoxyethylated oleic glyceride or vehicle only as a single oral dose in the morning.

SBP/DBP measurements occurred before and after 4 weeks of therapy in the sitting position.

Outcomes Effect of cyclosporine therapy on psoriasis using histopathologic examination, fluorescence microscopy of cutaneous infiltrates, leukotriene B4 analyses and clinical response for improvement or worsening of psoriasis.

BP measurements were included in the side effects investigation.

Notes MAP has been calculated from SBP and DBP.

Risk of bias


Description


Yes "Patients were assigned to one of the two groups by use of a table of random numbers"




Unclear "Patients were instructed to mix their medication or vehicle with milk or juice and to take the single oral daily dose in the morning." " a physician not involved in the care of the patients received reports on patients' blood levels of cyclosporine."


Unclear SBP/DBP and standard deviation were reported. MAP was calculated.


Unclear "patient compliance was enhanced by selecting patients known to us and thought to be reliable."

Comment: patients were pre-selected.

Free of other bias?


Ellis 1991

Methods RCT, double-blind, placebo controlled, parallel arm 8 weeks and 8 more weeks crossed-over

Participants 85 patients with severe chronic psoriasis on more than 25% of their body-surface; mean age 44 years (range 19 to 74)

Interventions Three groups received oral cyclosporine daily in an oral dose of 7.5mg/kg (N=15), 5mg/kg (N=20), 3mg/kg (N=25). The remaining group received vehicle only (N=25). The patients received a fixed dose of cyclosporine or vehicle for 8 weeks. This period was followed by an eight-week period during which the dose could be adjusted.

Outcomes The primary outcome was to assess the efficacy measuring the mean global scores for disease severity and the area-severity index.

The secondary outcome was to assess the safety evaluating clinical side effects as well as the renal function, the blood and tissue levels of cyclosporine, the delayed-type hypersensitivity and changes in clinical and laboratory variables (i.e. systolic and diastolic blood pressure).

Notes Baseline value of BP measurements had to be imputed according to the kind of patients population and the age (130/90 mmHg). MAP has been calculated from SBP and DBP results. Results of doses 3 and 5 mg/kg/d have been combined and the weighted mean calculated.

Risk of bias


Description


Yes "Eligible patients were assigned numbers in consecutive order; each number had been pre assigned to one of four treatment groups by means of a computer-generated random code in blocks of 17."




Yes "A physician who was not blinded to the patients' group assignment and who did not meet them reviewed their laboratory results, including their cyclosporine blood values; he alone prescribed the dose of medication (in millilitres) to an assistant. [...]Other physicians, who were blinded to the group assignment and laboratory findings through out the study, evaluated the patients and performed the

clinical assessments."


Unclear Baseline was missing and results were reported as percent change from baseline.



Free of other bias?

Unclear Manufacter supported

Ellis 1991 5mg-7.5mg/kg/d



Interventions Three groups received oral cyclosporine daily in an oral dose of 7.5mg/kg (N=15), 5mg/kg (N=20), 3mg/kg (N=25). The remaining group received vehicle only (N=25). The patients received a fixed dose of cyclosporine or vehicle for 8 weeks. This period was followed by an eight-week period during which the dose could be adjusted.



Notes Baseline value of BP measurements had to be imputed.

Risk of bias


Description


Yes "Eligible patients were assigned numbers in consecutive order; each number had been pre assigned to one of four treatment groups by means of a computer-generated random code in blocks of 17."




Yes "A physician who was not blinded to the patients' group assignment and who did not meet them reviewed their laboratory results, including their cyclosporine blood values; he alone prescribed the dose of medication (in millilitres) to an assistant. [...]Other physicians, who were blinded to the group assignment and laboratory findings through out the study, evaluated the patients and performed the clinical assessments."





Free of other bias?


Ellis 1991 A 3 mg/kg/d



Interventions Three groups received oral cyclosporine daily in a dose of 7.5mg/kg (N=15), 5mg/kg (N=20), 3mg/kg (N=25). The remaining group received vehicle only (N=25). The patients received a fixed dose of cyclosporine or vehicle for 8 weeks. This period was followed by an eight-week period during which the dose could be adjusted.



Notes Baseline value of BP measurements had to be imputed.

Risk of bias


Description

Adequate sequence

Yes "Eligible patients were assigned numbers in consecutive order; each number had been pre

generation? assigned to one of four treatment groups by means of a computer-generated random code in blocks of 17."




Yes "A physician who was not blinded to the patients' group assignment and who did not meet them reviewed their laboratory results, including their cyclosporine blood values; he alone prescribed the dose of medication (in millilitres) to an assistant. [...]Other physicians, who were blinded to the group assignment and laboratory findings through out the study, evaluated the patients and performed the clinical assessments."





Free of other bias?


Engst 1989 (5mg/kg/d)

Methods RCT, double-blind, placebo controlled, parallel arm, 4 weeks trial

Participants 12 patients with severe chronic psoriasis resistant to local therapy

Interventions Administration of either 5.5mg/kg/d oral cyclosporin or placebo for 4 weeks

Outcomes Primary outcome was the efficacy of CyA using PASI score for treatment of chronic psoriasis.

Secondary outcomes were blood pressure and creatinine.

Notes SBP and SBP were reported at baseline and after 4 weeks treatment. MAP has been calculated.

Risk of bias


Description



Allocation concealment? Unclear No information on allocation concealment




Yes SDB/DBP and standard deviation was reported. MAP was calculated

No withdrawn. Report of side effects (2patients).


Yes All outcomes are reported.

Free of other bias? Yes no manufactory sponsoring reported

Hansen 1997 (10mg/kg/d)

Methods RCT, double-blind, placebo controlled, cross-over arm, one day trial, interval of 2-4 weeks between the two interventions

Participants 18 healthy volunteers, 15men, 3women (mean age 23 years (range 21-29 years); mean weight 73kg (range 58-82kg); Patients were not allowed any medication (including analgesics) during the study period

Interventions Oral administration of 10 mg/kg/d Cyclosporine and placebo to each patient with an interval of 2-4 weeks between the two intervention days.

MAP was measured for 5min before ingestion of CsA or Placebo and at the end of each clearance period using a Finapres monitor Ohmeda, Englewood, Colorado, USA in the supine position.

Outcomes Mean arterial blood pressure (MAP) and Heart rate as well as the renal clearance were investigated.

Notes

Risk of bias


Description


Unclear "The subjects were allocated randomly in a double-blind fashion."






Yes All outcomes and patients are reported, no withdrawn

MAP and SEM are reported



Free of other bias? Unclear Manufacter sponsored

Lock 1996 (5 mg/kg/d)

Methods RCT, double-blind, placebo controlled, parallel arm, 52 weeks trial

Participants CsA group: 16 corticosteroid-dependent asthmatic patients (7M/9F), mean age 50 years (range 26-66), mean asthma duration 25 years (range 2-57), mean prednisolone duration 11 years (range 1-35) and mean prednisolone dosage 11 mg (range 5-20).

Placebo group: 20 corticosteroid-dependent asthmatic patients (12M/8F), mean age 52 years (range 27-67), mean asthma duration 28 years (range 4-56), mean prednisolone duration 13 years (range 1-37) and mean prednisolone dosage 12 mg (range 5-22.5).

Interventions 16 patients received CsA and 20 placebo in an oral dose of 5 mg/kg/d for 36 weeks double-blind treatment phase. Blood pressure was measured at each clinic visit, when spirometry was also done.

Outcomes Primary outcome: reduction in prednisolone dosage

Secondary outcome: lung function, bronchodilator usage, and symptom scores.

Notes SBP and DBP measures were reported in the safety data.

Risk of bias


Description




Yes "Patients were randomized to CsA or placebo group. All patients were reviewed at 14-d intervals by a physician ignorant of the randomization protocol."




Yes "There were five withdrawals from the study during the treatment phase: four from the CsA group and one from the placebo group.[...] Data from these patients were excluded from the efficacy analysis, although they were included in the analysis of safety data."

SBP/DBP and SEM are reported. MAP and standard deviation are calculated.



Free of other bias?


Minuk1988(5.1-6.4mg/kg/d)

Methods RCT, placebo controlled parallel

Participants 12 adult patients (11 women, 1 man; aged 52.5 ± 8.9 yr, mean ± SD) with serologic and histologically defined primary biliary cirrhosis

Interventions 12 patients were randomized to receive either Cyclosporin or placebo with a starting dose of 2.5mg/kg/d. The dose was adjust after 1 week treatment reaching 5.1 to 6.4 mg/kg/d

Outcomes The primary outcome was to determinate whether daily administration of CsA lead to a significant improvement in liver enzyme abnormalities.

Notes Only DBP measures were reported in the clinical variables.

Risk of bias


Description


Unclear Patients were randomized by sealed envelope to receive either CsA or placebo






Unclear Two of 6 placebo recipients died, the first 5 mo and the second 8.5 mo after the onset of the treatment phase of the study. The first patient died because of multisystem failure and the second one because of liver failure and sepsis after hepatic transplantation.

Only DBP results are reported



Free of other bias?

Unclear Study drug was provided by the manufacture

Nizankowska 1995 (2.5mg)

Methods RCT, double-blind, placebo controlled, parallel arm

Participants 34 nonsmoking adults (27 females and 7 males, aged 25-57 years, average 42 yrs) with severe chronic asthma. All required long-term oral steroid treatment at a minimum dose of 5-35 mg daily, in addition to standard therapy consisting of theophylline, inhaled beclomethasone and ß-mimetics.

Interventions After 12 weeks baseline period patients were randomly assigned to parallel treatment groups receiving 2.5 mg/kg/d CsA in two divided oral dose every 12h or placebo for 12 weeks (part I of the study). During part II the treatment with CsA or placebo was continued for 22 weeks. The corticosteroid dose was gradually reduced.

Outcomes The outcomes were to determinate the effects of cyclosporin treatment on asthma symptoms, lung function and corticosteroid tapering.

Notes SBP/DBP and heart rate were measured for the part I of the study. MAP was calculated.

Risk of bias


Description






Yes "Monitoring of cyclosporin levels, nephrotoxicity and dosage adjustment were performed by an unblinded clinician, who was neither involved in direct patient study contact or in assessment of the results. To maintain blinding, blood cyclosporin levels were determined in both groups."


Yes SBP/DBP and SD were measured for the part I of the study. MAP was calculated



Free of other bias?

Unclear Study drug was provided by the manufacture

Reitamo 1993 (2.5mg/kg/d)


Participants 38 patients (19 in CsA and 19 in placebo group, randomly assigned) aged 18 to 70 years with clinically defined PPP (palmoplantar pustulosis) of the palms and/or soles with at least 20 fresh pustules were included in the study.

Interventions Administration of either 2.5 mg/kg/d oral cyclosporin or placebo for 4 weeks (phase I of the study). Phase II was an open-dose finding study during 4 weeks and Phase III was an eight-weeks follow-up period.

Outcomes The outcome was to evaluate the efficacy of a treatment with cyclosporine for PPP compared to placebo. The parameter for evaluation of efficacy was the total number of fresh pustules in comparison with the patient's own baseline values.

Notes Only phase I is double-blinded. MAP was calculated.

Risk of bias


Description


Yes " The patients were given numbers 1 through 40 in consecutive order; each number had been pre-assigned to treatment with either cyclosporin or placebo."



Blinding? Yes The study drug was administered as capsules

All outcomes containing either CsA or placebo.


Yes SBP/DBP and SD were reported. MAP was calculated.



Free of other bias?

Unclear Study drug was provided by the manufactory

Sowden 1991 (5mg/kg/d)

Methods RCT, double-blind, placebo controlled, cross-over arm

Participants 33 patients with severe long-standing atopic dermatitis allocated in 2 groups: group 1 (10male, 6 female) placebo-cyclosporin mean age 29 years, range 16-58; group 2 (11 male, 6 female) cyclosporin-placebo mean age 30 years range 16-43.

Interventions Each patient was randomly allocated to receive either cyclosporine at a dose of 5 mg/kg/d for 8 weeks followed immediately by identical-looking placebo for 8 weeks or placebo followed by cyclosporin. After the treatment periods was a follow-up of 4 weeks.

Outcomes The primary outcome was to assess the efficacy and safety of cyclosporine in adults with severe refractory atopic dermatitis considering following criteria: disease activity, extent of disease, sleep and itch, topical steroid use and adverse events.

Notes No wash-out period before the cross-over so that only the blood pressure results (SBP/DBP) after the first 8 weeks have been considered, which means that the study design is a parallel arm.

MAP was calculated.

Risk of bias


Description






Yes "Results were monitored by an independent observer and not released to investigators during

the study.


Unclear SBP/DBP were reported. Standard deviation was imputed and MAP calculated.

"Of the 16 patients randomised to the placebo-cyclosporin sequence, 4 crossed over prematurely to the second phase because of the lack of effect of placebo treatment. Of the 17 patients randomised to the cyclosporin-placebo sequence, 6 patients did not complete the second, placebo period because of the treatment failure and 2 of these patients di not enter the four week follow-up period. No patients were withdrawn while receiving cyclosporin."



Free of other bias?


Sturrock 1994 (15-20mg)

Methods RCT, double-blind, placebo controlled, cross-over arm, 2 weeks wash-out period between study sessions

Participants 8 healthy male volunteers (mean age 23.4 ± 2.5 years; mean weight 77.2 ± 2.8 kg),

Interventions The patients were taking either CsA (15 mg/kg/d on days 1 to 3; 20 mg/kg/d on day 4) or placebo for four days. Blood pressure was measured every 20 minutes on day 1 using a semi-automated sphygmomanometer and at noon on days 2 and 3.

Outcomes The outcomes were to observe the effect of cyclosporin on following parameters: blood pressure, electrolyte handling, haemodynamic and renal water handling and sequential hormonal effect compared to placebo.

Notes MAP was measured.

Risk of bias

Item Authors' judgement Description








Yes MAP and SD were reported.



Free of other bias?

Unclear study drug has been provided by the manufactory

Sturrock 1995 (10mg/kg/d)

Methods RCT, double-blind, placebo controlled, cross-over arm, 2 weeks wash-out period between study sessions (9 days sessions)

Participants 9 healthy male volunteers ( mean age 32.3 years (95% confidence interval 26.9-37.7), mean weight 77.7 kg (60.0-89.1))

Interventions Subjects were treated with either CsA at a dose of 5mg/kg twice a day or placebo for 9 days. Blood pressure was measured in the supine position at the midpoint of each period by a semi-automated sphygmomanometer.

Outcomes The outcomes were to observe the effect of CsA on blood pressure, renal function, endothelin and lipoprotein compared to placebo.

Notes MAP was measured.

Risk of bias

Item Authors' judgement Description








Yes MAP and 95% confidence interval were reported.



Free of other bias?

Unclear study drug was provided by the manufactory

Tugwell 1990 (3.8mg/kg/d)


Participants 144 patients with severe rheumatoid arthritis from six centres were allocated to CsA or placebo group according to a prearranged randomisation plan, generated separately for each centre. Patients had to be over 18 years old and have six or more actively inflamed joints and also nine or more joints tender under pressure, at least 45 min of morning stiffness and an erythrocyte sedimentation rate of at least 28mm/hour.

Withdrawn:

10 withdrawn in CsA group, 4 because of adverse reaction

22 withdrawn in Pbo group, 21 because of lack of efficacy.

Interventions Patients were randomised to receive 2.5 mg/kg/d oral cyclosporin or placebo for 6 months. The treatment dose was increased cautiously with monitoring of serum CsA levels and creatinine. The mean dose was 3.8 mg/kg/d. Adjustment of doses were done by an unblinded clinician who was not in direct contact with study patients or involved in the assessment of outcome.

Outcomes The primary outcomes were to assess the treatment effect of CsA in rheumatoid arthritis patients measuring join score, swelling count, grip strength, pain and morning stiffness.

Notes Mean arterial blood pressure was measured at baseline and at 6 months.

Risk of bias


Description


Yes "144 patients from six centres were allocated to cyclosporin or placebo according to a prearranged randomisation plan, generated separately for each centre."




Yes "The monitoring of cyclosporin levels , nephrotoxicity, and hepatotoxicity, and adjustment of doses were done by an "unblinded" clinician who was not in direct contact with study patients or involved in the assessment of outcome. [...] To

maintain blinding of patients to treatment blood was collected in both groups. All patients in the placebo group had their drug volume adjusted as for the active treatment group."


Unclear The reporting of withdrawn is not precise.



Free of other bias?

Unclear study drug was provided by the manufactory

Wolinsky 1990 (6mg/kg/d)

Methods RCT, double-blind, placebo-controlled, parallel arms, multi-institutional study: randomization of 547 patients, design formulated by Sandoz Research Institute coordinators, 24 months study

Participants Patients with a diagnosis of clinically definite multiple sclerosis for a minimum of 1 year, an entry rating on the EDSS of grade 3.0 to 7.0 and an age of 18 to 55 years.

Patients with hypertension (systolic pressure >170 mm Hg or diastolic pressure > 110 mm Hg) were excluded.

273 patients were randomized to receive cyclosporine and 273 to receive placebo.

Interventions Investigation of oral cyclosporine versus placebo. The initial dose was 6mg/kg/d. Dosage was adjusted by an unblinded observer. A maximum dose of cyclosporine of 10 mg/kg/d was not exceeded.

Outcomes Efficacy was assessed by changes in scores on the Expanded Disability Status Scale (EDSS) and the incapacity status scales (ISS), and functional system scores of the Multiple Sclerosis Minimal Record of Disability (MSMRD).

SBP/DBP were measured in the sitting position. The results are reported in the toxicity outcome

Notes SBP/DBP were measured in the sitting position. MAP had to be calculated.

Risk of bias


Description

Adequate sequence

Yes "Study medication bottles were prepared, coded, packaged, and labelled by Sandoz Pharmaceuticals

generation? and preassigned to patient numbers using a computerized random allocation system and a block size of 4."


Yes "Patients, evaluating neurologists and study coordinators were blinded. Only the dose of the medication was adjusted by an unblinded observer in a reference laboratory."


Yes "The investigative team at each center was composed of at least an unblinded investigator who had no direct patient contact and whose sole role was to monitor toxicity in individual patients and adjust study medication levels: a blinded study coordinator who arranged all follow-up visits, entered data, and administered instrumented performance examinations; and two blinded neurologists who performed the clinical evaluations."


Yes "All withdrawn are in detail reported. ?Effort were made to follow all patients who were prematurely withdrawn from the study by continued monthly clinic visits for monitoring laboratory data and vital signs and at quarterly visits for clinical assessment for up to 6 months. In addition, after completion of the study, all patients who were withdrawn early were contacted using a standardized questionnaire."



Free of other bias?

Unclear Manufacturer supported

Características de los estudios excluidos [ordenados por ID del estudio]

Study Reason for exclusion

Appel 1988 Blood pressure data not reported

Barenbrock 1995

Patients received cyclosporine before the beginning of the study

Berg 1991 Failure to report adequate blood pressure data

Binet 2000 The study design was double-blinded and placebo controlled but there was no direct comparison CsA versus Placebo.

Brynskov 1990 Blood pressure has not been measured

Bursztyn 1997 Patients received cyclosporine before the beginning of the study

Calabrese 2002

Failure to report adequate blood pressure data

Camp 1993 Failure to report adequate blood pressure data. The paper is a report and not a trial.

Cattran 1995 Failure to report adequate blood pressure data

Dalavanga 1987


de Vries 1990 Blood pressure not reported

Dijkmans 1987 Failure to report adequate blood pressure data and almost 50% withdrawn

Drosos 1986 Failure to report adequate blood pressure data

Erkko 1998 The authors were contacted for missing information but did not answer the request.

Feagan 1994 Failure to report adequate blood pressure data

Feutren 1990 This trial was an analysis of 10 studies, which only 4 studies were double blinded.

Gerards 2003 The study design was double-blinded and placebo controlled but there was no direct comparison CsA versus Placebo.

Grattan 2000 Failure to report adequate blood pressure data

Gupta 1991 This trial used the same data like Ellis 1986 already included

Kuypers 2004 Patients received cyclosporine before the beginning of the study

Lai 1987 Failure to report adequate blood pressure data

Lai 1991 Failure to report adequate blood pressure data

Leenen 2007 Patients received cyclosporine before the beginning of the study

Lieberman 1996


Lombard 1993 The authors were contacted for missing information and declared not to have access to the data anymore.

Madsen 1995 The study design was double-blinded and placebo controlled but there was no direct comparison CsA versus Placebo.

Madsen 1996 The study design was double-blinded and placebo controlled but there was no direct comparison CsA versus Placebo.

Martin 1991 Failure to report adequate blood pressure data

Mazzeo 2008 Cyclosporin was injected as perfusion and was not comparable with oral dose.

Meffert 1997 The patients reporting was unclear and the report of blood pressure data was not adequate

Miranda 2004 The study design was double-blinded and placebo controlled but there was no direct comparison CsA versus Placebo.

Munro 1994 The authors were contacted for missing information and declared not to have access to the data anymore.

Papp 2008 The authors were contacted for missing information but did not answer the request.

Parrott 2005 The study design was double-blinded and placebo controlled but there was no direct comparison CsA versus Placebo.

Rudge 1989 Failure to report adequate blood pressure data

Salek 1993 Same trial like Sowden 1991 already included.

Sandborn 1993 Blood pressure not reported

Sihra 1997 Failure to report adequate blood pressure data

Stange 1995 Failure to report adequate blood pressure data

van Joost 1988 The reason for exclusion was failure to report adequate blood pressure data

van Joost 1994 No blood pressure results were reported and there was incoherence in reported N.

Van Rijthoven 1986


Vena 2006 Blood pressure not reported

Wiesner 1990 The authors were contacted for missing information but did not answer the request.

Table 1. Overview of the 17 included studies classified by dose range

Dose range Number CsA Placebo Mean MAP or MAP Mean

(multiple dose)

of studies

patients (N)

patients (N)

duration

(days or weeks)

SBP/DBP measured

difference [95% CI] between CsA and Placebo

low dose (1-4mg/kg/d)

6 161 155 14.6w 5x SBP/DBP

1x MAP

4.99 [2.78, 7.20]

medium dose (5-10mg/kg/d)

7 346 343 17w 5x SBP/DBP

1x MAP

1x DBP

6.43 [4.81, 8.06]

high dose

(>10 mg/kg/d)

2 19 18 1x 4w

1x 1d

1x SBP/DBP

1x MAP

11.37 [7.15, 15.60]

Dose range (single dose)

low dose (1-4mg/kg/d)

1 14 14 1d MAP 3.00 [0.06, 5.94]

medium dose (5-10mg/kg/d)

1 18 18 1d MAP 10.90 [7.57, 14.23]

high dose (>10 mg/kg/d)

1 10 10 1d MAP 4.00 [-2.87, 10.87]

Table 2. Overview of the 17 included studies classified by indication

Indication Name Number of studies

Treatment dose (mg/kg/d)

CsA patients (N)

Placebo patients (N)

Duration

(days,weeks or months)

MAP or SBP/DBP

MAP Mean difference [95% CI] between CsA and Placebo

Psoriasis Ellis 1986 14 11 10 4w SBP/DBP

Ellis 1991 3-7.5 60 25 8w SBP/DBP

Engst 1989 5 6 6 4w SBP/DBP

Mean [range] 3 7.4 [3-14] 77 66 5.3w 4.43 [0.37, 8.48]

Effect of CsA in healthy volunteers

De Lima 1998

20 10 10 1d MAP and SBP/DBP

Hansen 1997

10 18 18 1d MAP

Sturrock 1994

15-20 8 8 4d MAP

Sturrock 1995

10 9 9 9d MAP

Mean [range] 4 14.4

[10-20]

45 45 3.75d 9.42 [6.09, 12.74]

Rheumatoid arthritis

Bendix 1996 2.5 16 20 6m SBP/DBP

Dougados 1988

4.6 22 24 4m SBP/DBP

Tugwell 1990

3.8 62 50 6m MAP

Mean [range] 3 3.63

[2.5-3.8]

100 94 5.3m 6.25 [2.69, 9.82]

Corticostreroid dependent asthma

Lock 1996 5 16 20 9m SBP/DBP

Nizankowska 1995

2.5 17 17 3m SBP/DBP

Mean [range] 2 3.75

[2.5-5]

33 37 6m SBP/DBP

4.71 [0.41, 9.01]

Primary biliary cirrhosis

Minuk 1988 1 4.7-6.2 6 6 12m DBP 1.00 [-7.76, 6.52]

Palmoplantar pustulosis

Reitamo 1993

1 2.5 19 19 4w SBP/DBP

0.8 [-4.92,

6.52]

Atopic dermatitis

Sowden 1990

1 5 12 17 8w SBP/DBP

6.8 [-0.57, 14.17]

Renal transplant recipients

Aberg 2000 1 4 14 14 1d MAP 3.00 [0.06, 5.94]

Multiple sclerosis

Wolinsky 1990

1 6 262 260 24m SDP/DBP

7.07 [5.05, 9.09]

FIGURAS

Figure 1

Methodological characteristics of included studies: (+) indicates low risk of bias, (?) unclear and (-) high risk of bias in a specific item.

Analysis 1.1

Comparison 1 MAP Multiple Dose, Outcome 1 Low dose (1-4mg/kg/d).

Analysis 1.2

Comparison 1 MAP Multiple Dose, Outcome 2 Medium dose (5-10mg/kg/d).

Analysis 1.3

Comparison 1 MAP Multiple Dose, Outcome 3 High dose (>10mg/kg/d).

Analysis 2.1

Comparison 2 MAP Single Dose, Outcome 1 Low dose (1-4mg/kg/d).

Analysis 2.2

Comparison 2 MAP Single Dose, Outcome 2 Medium dose (5-10mg/kg/d).

Analysis 2.3

Comparison 2 MAP Single Dose, Outcome 3 High dose (>10mg/kg/d).

Analysis 3.1

Comparison 3 Indication, Outcome 1 Psoriasis.

Analysis 3.2

Comparison 3 Indication, Outcome 2 Healthy volunteers.

Analysis 3.3

Comparison 3 Indication, Outcome 3 Rheumatoid arthritis.

Analysis 3.4

Comparison 3 Indication, Outcome 4 Corticosteroid dependent asthma.

Analysis 3.5

Comparison 3 Indication, Outcome 5 Primary biliary cirrhosis.

Analysis 3.6

Comparison 3 Indication, Outcome 6 Palmoplantar pustulosis.

Analysis 3.7

Comparison 3 Indication, Outcome 7 Atopic dermatitis.

Analysis 3.8

Comparison 3 Indication, Outcome 8 Renal transplant recipients.

Analysis 3.9

Comparison 3 Indication, Outcome 9 Multiple sclerosis.

Traducción realizada por el Centro Cochrane Iberoamericano.

Usado con permiso de John Wiley & Sons, Ltd.

Documents

La Biblioteca Cochrane Plus - … · Las indicaciones oficiales de Canadá para la ciclosporina son el trasplante de órganos sólidos, el ... (e-CPS 2008). Muchas otras enfermedades