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Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)
Medwave 2016;16(Suppl5):e6632 doi: 10.5867/medwave.2016.6632
Does the addition of ezetimibe to statins reduce cardiovascular risk?
Francisca I Araya, Bruno Grassi
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Problema

La enfermedad cardiovascular constituye la principal causa de mortalidad en población adulta. Los niveles elevados de colesterol LDL se asocian a mayor riesgo de enfermedad coronaria, y este riesgo es menor con niveles más bajos hasta llegar a un nivel de aproximadamente 80 mg/dl (2,1 mmol/l) [1]. Es por esto que múltiples guías clínicas han establecido metas de LDL, y para lograrlas se requiere muchas veces un tratamiento intensivo [1]. Si bien esto puede intentarse con altas dosis de estatinas, un porcentaje sustantivo de los pacientes no logra la meta. Además, aunque se alcancen las metas deseadas, el riesgo cardiovascular de los pacientes sigue siendo mayor al de la población sana, lo que se ha denominado “riesgo residual”. Se han planteado nuevas opciones, como el ezetimibe, un inhibidor de la absorción intestinal de colesterol que bloquea la absorción de sales biliares y de colesterol proveniente de la dieta, sin afectar las vitaminas liposolubles o los triglicéridos. Considerando que su mecanismo de acción difiere del de las estatinas, las cuales inhiben la síntesis de colesterol, se ha propuesto que podrían ser una combinación efectiva. Sin embargo, no está claro si agregar ezetimibe al tratamiento con estatinas tiene beneficios, especialmente en reducir el riesgo cardiovascular a largo plazo.

Métodos

Utilizamos la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 30 bases de datos, 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

  • La adición de ezetimibe al tratamiento con estatinas probablemente resulta en poca o nula diferencia en la mortalidad total.
  • La adición de ezetimibe al tratamiento con estatinas podría llevar a una pequeña reducción en el riesgo de infarto y accidente cerebrovascular, pero la certeza de la evidencia es baja.
  • La adición de ezetimibe al tratamiento con estatinas no aumenta los efectos adversos serios.
Acerca del conjunto de evidencia para esta pregunta

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

Encontramos nueve revisiones sistemáticas [2], [3],
[4], [5], [6], [7], [8], [9], [10] que incluyen 67 estudios controlados aleatorizados sobre ezetimibe e hipercolesterolemia, reportados en 69 referencias
[11], [12], [13], [14], [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].

Este resumen analiza los 37 estudios que compararon ezetimibe asociado a estatinas versus la monoterapia con estatinas en la misma dosis, que corresponde a la pregunta clínicamente más relevante [12], [17], [18], [19], [23], [24], [26], [27], [28], [29], [31], [34], [35], [36], [37], [40], [42], [43], [46], [48], [49], [50], [52], [53], [54], [58], [65], [66], [67], [68], [69], [71], [73], [74], [76], [77], [78].

Qué tipo de pacientes incluyeron los estudios

Nueve estudios incluyeron pacientes con enfermedad coronaria conocida [26], [27], [37], [42], [48], [53], [54], [71], [74], de los cuales dos incluyeron pacientes con niveles de LDL menor a 160 mg/dl [42], [71]; un estudio incluyó pacientes con hipercolesterolemia y riesgo cardiovascular alto [58]; un estudio fue realizado en pacientes con síndrome coronario agudo [29]; un estudio incluyó pacientes con infarto agudo al miocardio [69]; un estudio fue realizado en pacientes diabéticos con hipercolesterolemia [17]; dos estudios incluyeron pacientes con enfermedad arterial periférica [50], [76]; dos estudios fueron realizados en pacientes con enfermedad renal crónica [31], [73]; 18 estudios fueron realizados en pacientes con hipercolesterolemia primaria [12], [18], [19], [23], [24], [28], [34], [35], [36], [40], [43], [46], [65], [66], [67], [68], [77], [78] (uno centrado solo en sujetos afro-americanos [18]); un estudio incluyó pacientes con hipercolesterolemia familiar homocigota [52]; y un estudio fue realizado en sujetos sanos [49]. 

Qué tipo de intervenciones incluyeron los estudios

Cinco estudios compararon el efecto de atorvastatina y ezetimibe versus atorvastatina más placebo [26], [42], [66], [67], [74]; 22 estudios compararon el uso de simvastatina más ezetimibe versus simvastatina más placebo [17], [18], [19], [23], [28], [29], [31], [35], [37], [40], [43], [46], [49], [53], [54], [68], [69], [71], [73], [76], [77], [78]; un estudio comparó el efecto de atorvastatina y simvastatina asociado a ezetimibe versus ambas estatinas por separado más placebo [52]; un estudio comparó el efecto de simvastatina más ezetimibe versus atorvastatina más placebo [65]; seis studios compararon pravastatina, lovastatina o fluvastatina o varias estatinas dentro del mismo estudio asociado a ezetimibe versus la estatina sola [12], [24], [34], [36], [48], [58]; y dos estudios compararon rosuvastatina más ezetimibe versus rosuvastatina asociado a placebo [27], [50].

Qué tipo de desenlaces midieron

Si bien los estudios primarios reportan los desenlaces de manera diversa, la forma en que las diferentes revisiones sistemáticas identificadas los agruparon es la siguiente:

  • Mortalidad total
  • Mortalidad cardiovascular
  • Eventos cardiovasculares (infarto agudo al miocardio, accidente cerebrovascular, necesidad de reperfusión coronaria, angina inestable de alto riesgo)
  • Infarto agudo al miocardio 
Resumen de los resultados

La información sobre los efectos del ezetimibe asociado a estatinas que se analizó en este resumen, está basada en 37 estudios controlados aleatorizados [12], [17], [18], [19], [23], [24], [26], [27], [28], [29], [31], [34], [35], [36], [37], [40], [42], [43], [46], [48], [49], [50], [52], [53], [54], [58], [65], [66], [67], [68], [69], [71], [73], [74], [76], [77], [78]. Sólo nueve estudios reportaron mortalidad total [29], [31], [42], [43], [50], [66], [73], [74], [76], siete estudios analizaron infarto al miocardio no fatal [27], [29], [43], [50], [73], [74], [76], seis accidente cerebrovascular [31], [43], [50], [73], [74], [76], tres revascularización coronaria [27], [29], [74] y 17 estudios analizaron efectos adversos serios [17], [23], [24], [27], [29], [30], [31], [37], [42], [46], [53], [54], [64], [66], [71], [73], [78]. El resumen de los resultados es el siguiente:

  • La adición de ezetimibe al tratamiento con estatinas probablemente resulta en poca o nula diferencia en la mortalidad total. La certeza de la evidencia es moderada.
  • La adición de ezetimibe al tratamiento con estatinas podría llevar a una pequeña reducción en el riesgo de infarto, pero la certeza de la evidencia es baja.
  • La adición de ezetimibe al tratamiento con estatinas podría llevar a una pequeña reducción en el riesgo de accidente cerebrovascular, pero la certeza de la evidencia es baja.
  • La adición de ezetimibe al tratamiento con estatinas no aumenta los efectos adversos serios. La certeza de la evidencia es alta.

Otras consideraciones para la toma de decisión

A quién se aplica y a quién no se aplica esta evidencia
  • La mayor proporción de los datos presentados proviene de estudios con pacientes con niveles de LDL ≤ 140 mg/dl, con enfermedad renal crónica o con síndrome coronario agudo reciente.
  • En pacientes con un menor riesgo cardiovascular es razonable esperar un resultado similar, aunque si el efecto del ezetimibe fuera cierto, en estos pacientes sería aún de menor cuantía, dado que son pacientes cuyo riesgo basal es más bajo.
Sobre los desenlaces incluidos en este resumen
  • Se incluyeron los desenlaces más relevantes para la toma de decisión.
  • Es importante destacar que el nivel de colesterol LDL que se logra no constituye un desenlace importante para el paciente, sino un desenlace sustituto. Estos sólo deben ser utilizados si no existe información sobre los primeros.
  • Otro desenlace habitualmente utilizado por las principales guías es la revascularización. Este no fue incluido por ser de menor importancia relativa que los otros. De todas formas, no se observó ningún efecto sobre este desenlace (RR 0,96; IC 95% 0,90 a 1,01; certeza de la evidencia alta).
Balance riesgo/beneficio y certeza de la evidencia
  • Se trata de un tratamiento que probablemente no tiene efecto sobre la mortalidad, y que podría tener un efecto pequeño sobre el riesgo de presentar eventos cardiovasculares, aunque con evidencia de baja certeza. Pero por otra parte, no tiene efectos adversos serios. 
Qué piensan los pacientes y sus tratantes
  • Al tratarse de una intervención con un beneficio pequeño e incierto, pero sin efectos adversos y de relativo alto costo, es probable que exista gran variabilidad en la decisión tomada por distintos pacientes y tratantes, dependiendo de cuánto valor pongan estos en cada uno de estos factores.
Consideraciones de recursos
  • Dado el alto costo del ezetimibe, y la baja magnitud del beneficio es poco probable que se trate de una terapia costo-efectiva, aunque una evaluación formal de este aspecto es deseable en los escenarios en que se esté considerando su utilización.
Diferencias entre este resumen y otras fuentes
  • Este resumen concuerda parcialmente con las distintas revisiones sistemáticas, las cuales difieren entre sí. Por ejemplo, una de las revisiones concluye que a pesar de ser una diferencia pequeña, por la importancia de los desenlaces, estas no dejan de ser importantes para los pacientes [3], mientras que otras sugieren que el ezetimibe no agrega beneficio importante al tratamiento con estatinas como monoterapia [5].
  • Las guías de la European Society of Cardiology recomiendan el uso de ezetimibe en pacientes con niveles de LDL ≥70mg/dl a pesar de tener la dosis máxima tolerada de estatinas [80]. Esta recomendación no difiere de este resumen ya que recomienda ezetimibe exclusivamente frente al fracaso de tratamiento con estatinas, reconociendo la pequeña reducción en los eventos cardiovasculares y nula diferencia en mortalidad. 
¿Puede que cambie esta información en el futuro?
  • La probabilidad que futura evidencia cambie las conclusiones de este resumen es alta para algunos desenlaces críticos para la toma de decisión, debido a la incertidumbre existente.
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: Ezetimibe para la hipercolesterolemia

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.

 

Statins are the mainstay of lipid-lowering therapy nowadays, since they reduce cardiovascular risk when used as primary or secondary prevention. However, only one third of the patients reach the goals established in several guidelines, and even if they do, they keep a risk higher than healthy controls. One of the new lipid-lowering agents is ezetimibe. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified nine systematic reviews comprising 67 trials overall. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded adding ezetimibe to statins probably results in little or no difference in overall mortality. It might lead to a small reduction in the risk of myocardial infarction and stroke, but the certainty of the evidence is low.

Authors: Francisca I Araya[1], Bruno Grassi[1,2]

Affiliation:
[1] Proyecto Epistemonikos, Santiago, Chile
[2] Departamento de Nutrición y Diabetes, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

E-mail: bagrassi@gmail.com

Author address:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Diagonal Paraguay 476
Santiago Centro
Chile

Citation: Araya FI, Grassi B. Does the addition of ezetimibe to statins reduce cardiovascular risk?. Medwave 2016;16(Suppl5):e6632 doi: 10.5867/medwave.2016.6632

Publication date: 5/12/2016

PubMed record

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July 2022, Vol 22, Issue 6
icon Research papers
Association of biomarkers and severity of COVID-19: A crosssectional study

Systematization of initiatives in sexual and reproductive health about good practices criteria in response to the COVID-19 pandemic in primary health care in Chile

Clinical, psychological, social, and family characterization of suicidal behavior in Chilean adolescents: a multiple correspondence analysis

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