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Resúmenes Epistemonikos
Medwave2017;17(Suppl2):e6942 doi: 10.5867/medwave.2017.6942
Sevelamer comparado con quelantes de fósforo en base a calcio para la insuficiencia renal crónica
Sevelamer versus calcium-based phosphate binders for chronic kidney disease
Gonzalo A Bravo-Soto, Trinidad Madrid
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Resumen

Los trastornos minerales y óseos asociados a la enfermedad renal crónica son frecuentes. Para su tratamiento existen quelantes de fósforo en base a calcio y otros no cálcicos como el sevelamer, pero no está claro cuál constituye una mejor opción. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples fuentes de información, identificamos 12 revisiones sistemáticas que en conjunto incluyen 61 estudios primarios, de los cuales 41 corresponden a ensayos aleatorizados. Extrajimos los datos, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. Concluimos que el sevelamer, en comparación con los quelantes de fósforo en base a calcio, podría disminuir los eventos de hipercalcemia, pero con una mayor incidencia de efectos gastrointestinales. Por otra parte, no está claro si existen diferencias en cuanto a mortalidad porque la certeza de la evidencia es muy baja.


 
Problema

Una de las complicaciones de los pacientes con insuficiencia renal crónica son los trastornos minerales y óseos. Éstos incluyen tres componentes principales [1]:

  • Alteración de niveles de calcio, fósforo, hormona paratiroidea y vitamina D.
  • Alteración del recambio óseo, mineralización, resistencia, volumen y crecimiento lineal
  • Calcificaciones extraóseas.

La hiperfosfemia juega un rol en múltiples niveles, por lo que su adecuado manejo con quelantes de fósforo se considera fundamental. Existen dos alternativas terapéuticas principales; los quelantes de fósforo en base a calcio (por ej. acetato de calcio y carbonato de calcio) y los no cálcicos, en particular el sevelamer. Sevelamer es un polímero de clorhidrato de alilamina. Sin embargo, no está claro cuál de las alternativas constituye una mejor opción.

Métodos

Utilizamos la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples fuentes de información, para identificar revisiones sistemáticas y sus estudios primarios incluidos. Con esta información generamos un resumen estructurado, siguiendo un formato preestablecido, que incluye mensajes clave, un resumen del conjunto de evidencia (presentado como matriz de evidencia en Epistemonikos), metanálisis del total de los estudios, tablas de resumen de resultados con el método GRADE, y tabla de otras consideraciones para la toma de decisión.

Mensajes clave

  • El sevelamer, en comparación con los quelantes de fósforo en base a calcio, podría disminuir los eventos de hipercalcemia, pero con una mayor incidencia de efectos gastrointestinales.
  • No está claro si existen diferencias entre sevelamer y los quelantes de fósforo en base a calcio en cuanto a mortalidad porque la certeza de la evidencia es muy baja. 
Acerca del conjunto de evidencia para esta pregunta

Cuál es la evidencia. 
Véase matriz de evidencia en Epistemonikos más abajo.

Encontramos 12 revisiones sistemáticas en 13 referencias [2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14] que incluyen 61 estudios primarios en 75 referencias [15], [16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26], [27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37], [38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48], [49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59], [60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70], [71],[72],[73],[74],[75],[76],[77],[78],[79],[80],[81], [82],[83],[84],[85],[86],[87],[88],[89]. De éstos, 41 estudios en 54 referencias son ensayos aleatorizados. Esta tabla y el resumen en general se basan en estos últimos, dado que los estudios observacionales no aumentaban la certeza de la evidencia existente, ni entregaban información adicional relevante.

Qué tipo de pacientes incluyeron los estudios*

Respecto a la etapa de la nefropatía, 27 ensayos [15], [18],[20],[22],[26],[33],[34],[35],[36],[37],[41],[43], [44],[47],[50],[52],[53],[54],[56],[57],[64],[68],[69], [74],[75],[81],[84] incluyeron pacientes en hemodiálisis, tres [31],[39],[61] en peritoneodiálisis, nueve [23],[27],[29],[38],[46],[63],[73],[85],[88] incluyeron pacientes en etapa III o IV sin diálisis, un ensayo [77] no especificó el tipo de diálisis, sino sólo que llevaran más de seis meses en esta terapia y un ensayo [89] sólo requirió que estuviesen en etapa V.**

Qué tipo de intervenciones incluyeron los estudios*

Todos los ensayos utilizaron sevelamer como intervención en dosis ajustada según fósforo. No se logró extraer algún dato más específico de la dosis desde las revisiones sistemáticas.

Seis ensayos [33],[34],[36],[47],[53],[75] utilizaron como cointervención vitamina D por cualquier vía de administración, uno [20] usó vitamina D oral, tres [18],[39],[69] usaron vitamina D endovenosa, un ensayo [68] utilizó atorvastatina y uno [77] carbonato de calcio en dosis bajas.

Respecto a la comparación, 14 ensayos [18],[20],[27], [46],[47],[56],[57],[61],[63],[64],[68],[69],[88],[89] utilizaron acetato de calcio, 20 ensayos [15],[26],[29], [31],[36],[37],[38],[39],[41],[43],[50],[52],[53],[54], [73],[74],[75],[77],[84],[85] usaron carbonato de calcio, cinco [22],[33],[35],[44],[81] usaron carbonato de calcio y acetato de calcio.

Qué tipo de desenlaces midieron

Los desenlaces, de acuerdo a como fueron agrupados en las revisiones sistemáticas identificadas, fueron:

  • Mortalidad
  • Mortalidad cardiovascular
  • Hospitalizaciones
  • Desenlace compuesto de eventos cardiovasculares
  • Calcificación coronaria
  • Calcificación vascular
  • Eventos gastrointestinales (náuseas, vómitos, diarrea, constipación y distención abdominal.)
  • Hipercalcemia
  • Fósforo sérico
  • Calcio sérico
  • Producto calcio-fósforo
  • Vitamina D
  • Bicarbonato sérico
  • iPTH
  • Densidad Ósea
El seguimiento promedio fue 36,5 semanas, con un rango de 3 a 144 semanas.

La información sobre los estudios primarios es extraída desde las revisiones sistemáticas identificadas, no directamente desde los estudios, a menos que se especifique lo contrario.
**Etapa de insuficiencia renal crónica según MDRD-4

Resumen de los resultados

La información sobre los efectos de sevelamer en comparación a quelantes de fósforo basados en calcio está basada en el total de ensayos identificados en este resumen, que incluyen 5928 pacientes.

Treinta y un ensayos [18],[20],[22],[23],[26],[27],[29],[33],[36],[37],[38],[39],[41],[47],[50],[53],[54],[56],[57],[61],[63],[68],[69],[73],[74],[75], [81],[84],[85],[88],[89] midieron mortalidad que incluyen 5011 pacientes. Veinte ensayos [20],[23],[27],[29],[33],[35],[39],[41],[43],[50],[53],[54],[56],[57],[63],[68],[74],[75],[81],[88] midieron eventos adversos gastrointestinales que incluyen 2863 pacientes. Diecinueve ensayos [20],[22],[23],[26],[27],[33],[36],[38],[39],[43],[47],[56],[57],[68],[69],[74],[75],[81],[88] midieron hipercalcemia que incluyen 2867 pacientes.

El resumen de los resultados es el siguiente: 

  • El sevelamer, en comparación con los quelantes de fósforo en base a calcio, podría disminuir los eventos de hipercalcemia, pero la certeza de esta evidencia es baja.
  • El sevelamer, en comparación con los quelantes de fósforo en base a calcio, podría aumentar la incidencia de efectos gastrointestinales. La certeza de esta evidencia es baja.
  • No está claro si existen diferencias en cuanto a mortalidad entre sevelamer y quelantes de fósforo en base a calcio porque la certeza de la evidencia es muy baja. 

Siga el enlace para acceder a la versión interactiva de tabla SOF

 

Otras consideraciones para la toma de decisión

A quién se aplica y a quién no se aplica esta evidencia

  • Los resultados de este resumen se aplican a pacientes con enfermedad renal crónica en riesgo de desarrollar trastorno mineral y óseo, independiente de la etiología.
  • Si bien la mayoría de los ensayos incluyó mayoritaria o exclusivamente a pacientes en diálisis, es razonable extrapolar las conclusiones de este resumen a cualquier paciente en riesgo de desarrollar enfermedad mineral y ósea, al menos mientras no contemos con evidencia directa en estos casos.
Sobre los desenlaces incluidos en este resumen
  • Los desenlaces incluidos en este resumen son aquellos considerados como críticos para la toma de decisión por los autores del resumen. En general coinciden con aquellos mencionados por las revisiones sistemáticas y guías identificadas.
  • Se decidió incluir el desenlace hipercalcemia a pesar de ser un desenlace sustituto porque consiste en uno de los efectos adversos más temidos al utilizar quelantes de fósforo en base a calcio, lo que pudiese ser un elemento importante al decidir su uso.
Balance riesgo/beneficio y certeza de la evidencia
  • Debido a la incertidumbre en relación al efecto sobre mortalidad, y la baja certeza sobre los efectos adversos gastrointestinales y la hipercalcemia, no es posible realizar un adecuado balance entre beneficios y riesgos de sevelamer por sobre quelantes de fósforo en base a calcio. 
Consideraciones de recursos
  • El sevelamer tiene un alto costo comparado con los quelantes de fosforo en base a calcio y sus beneficios clínicos no estan claros.
  • La diferencia de costo entre ambos tratamientos probablemente será clave en la elección, dependiendo del contexto y los recursos que se dispongan.
Qué piensan los pacientes y sus tratantes
  • Los resultados presentados en este resumen debieran llevar a una importante variabilidad en la toma de decisión; quienes privilegien un beneficio incierto podrían inclinarse a favor de sevelamer, y quienes pongan más acento en evitar efectos adversos, en el costo, o en la certeza de la evidencia, podrían inclinarse por los quelantes en base a calcio.
  • Es posible que también exista variabilidad entre los médicos, en especial frente a la existencia de recomendaciones discordantes en las principales guías. 
Diferencias entre este resumen y otras fuentes
  • Este resumen presenta información concordante con gran parte de las revisiones sistemáticas incluidas.
  • Respecto a la información entregada por las diferentes guías clínicas, existe discrepancia entre ellas. Las guías KDIGO [90] y la guía de la National Kidney Foundation (KDOQI) [91] refieren que no existen diferencias entre quelantes de fósforo en base a calcio y sevelamer, sino que más bien su elección pasa por el perfil de cada paciente (eventos adversos gastrointestinales, hipercalcemia, costo, entre otros parámetros). En cambio, la guía de la Canadian Society of Nephrology [92] señala que no hay suficiente evidencia para recomendar los quelantes de fósforo que no contienen calcio.
¿Puede que cambie esta información en el futuro?
  • La probabilidad de que futura investigación cambie las conclusiones de este resumen es alta, debido a la certeza de la evidencia existente.
  • No identificamos ensayos en curso en la International Clinical Trials Registry Platform de la Organización Mundial de la Salud, ni ensayos publicados no incluidos en las revisiones sistemáticas identificadas que evalúen la pregunta clínica de este resumen.
  • Cabe destacar que las revisiones sistemáticas identificadas incluyen una proporción relativamente baja de los estudios incluidos en este resumen, por lo que nuevas revisiones podrían aportar información relevante.
Cómo realizamos este resumen

Mediante métodos automatizados y colaborativos recopilamos toda la evidencia relevante para la pregunta de interés y la presentamos en una matriz de evidencia.

Siga el enlace para acceder a la versión interactiva: Sevelamer comparado con quelantes de fósforo en base a calcio en insuficiencia renal crónica

Notas

Si con posterioridad a la publicación de este resumen se publican nuevas revisiones sistemáticas sobre este tema, en la parte superior de la matriz se mostrará un aviso de “nueva evidencia”.  Si bien el proyecto contempla la actualización periódica de estos resúmenes, los usuarios están invitados a comentar en Medwave o contactar a los autores mediante correo electrónico si creen que hay evidencia que motive una actualización más rápida.

Luego de crear una cuenta en Epistemonikos, al guardar las matrices recibirá notificaciones automáticas cada vez que exista nueva evidencia que potencialmente responda a esta pregunta. El detalle de los métodos para elaborar este resumen están descritos aquí: http://dx.doi.org/10.5867/medwave.2014.06.5997.

La Fundación Epistemonikos es una organización que busca acercar la información a quienes toman decisiones en salud, mediante el uso de tecnologías. Su principal desarrollo es la base de datos Epistemonikos (www.epistemonikos.org).

Los resúmenes de evidencia siguen un riguroso proceso de revisión por pares interno.

Declaración de conflictos de intereses
Los autores declaran no tener conflictos de intereses con la materia de este artículo.

Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

Chronic kidney disease-mineral and bone disorder is prevalent. There is controversy regarding whether calcium-based phosphate binders or sevelamer - a non-calcium phosphate binder – constitute a better therapeutic alternative. Searching in Epistemonikos database, which is maintained by screening multiple information sources, we identified 12 systematic reviews comprising 61 studies of which 41 correspond to randomized trials addressing the question of this article. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded sevelamer may decrease hypercalcemia, but with a higher incidence of gastrointestinal effects than calcium based phosphate binders. It is unclear if there are differences in mortality because the certainty of the evidence is very low.

Autores: Gonzalo A Bravo-Soto[1,2], Trinidad Madrid[2,3]

Filiación:
[1] Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[2] Proyecto Epistemonikos, Santiago, Chile
[3] Departamento de Medicina Interna, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

E-mail: madrid.trini@gmail.com

Correspondencia a:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Lira 63
Santiago Centro
Chile

Citación: Bravo-Soto GA, Madrid T. Sevelamer versus calcium-based phosphate binders for chronic kidney disease. Medwave2017;17(Suppl2):e6942 doi: 10.5867/medwave.2017.6942

Fecha de envío: 24/2/2017

Fecha de aceptación: 1/3/2017

Fecha de publicación: 12/5/2017

Ficha PubMed

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Hervás JG, Prados D, Cerezo S. Treatment of hyperphosphatemia with sevelamer hydrochloride in hemodialysis patients: a comparison with calcium acetate. Kidney Int Suppl. 2003 Jun;(85):S69-72 | PubMed |

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Lin HH, Liou HH, Wu MS, Lin CY, Huang CC. Long-term sevelamer treatment lowers serum fibroblast growth factor 23 accompanied with increasing serum Klotho levels in chronic haemodialysis patients. Nephrology (Carlton). 2014 Nov;19(11):672-8 | CrossRef | PubMed |

Lin YF, Chien CT, Kan WC, Chen YM, Chu TS, Hung KY, et al. Pleiotropic effects of sevelamer beyond phosphate binding in end-stage renal disease patients: a randomized, open-label, parallel-group study. Clin Drug Investig. 2011;31(4):257-67 | CrossRef | PubMed |

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