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Problema de Salud AUGE N°75

Tratamiento de personas de 15 años y más con Trastorno Bipolar

Juicio del Panel y Evidencia

En personas con trastorno bipolar en fase de mantención con embarazo en curso (segundo y tercer trimestre) el Ministerio de Salud SUGIERE usar litio como monoterapia o usar antipsicóticos atípicos como monoterapia.
Comentarios del panel:
► La evidencia no muestra seguridad mayor en el uso de litio ni de antipsicótico atípicos durante el segundo o tercer trimestre del embarazo, por lo tanto la elección debe hacerse de forma personalizada, considerando antecedentes maternos de comorbilidad y uso de fármacos y los valores y preferencias de la mujer embarazada.
► Esta recomendación no aplica al uso de fármacos durante el primer trimestre del embarazo, donde los riesgos son diferentes y claramente establecidos.

El Panel de Expertos analizó y debatió cada uno de las preguntas de la “Tabla de la evidencia a la decisión”, considerando tanto la evidencia de investigación, experiencia clínica, conocimiento de gestión o experiencia de los pacientes. Una vez consensuada la postura del panel respecto a las preguntas, emitieron un juicio seleccionando la opción de respuesta que mejor representaba la opinión del conjunto (destacada con color). Finalmente cuando el panel emitió su juicio sobre todas las preguntas, se emitió la recomendación.

A continuación se presenta la “Tabla de la evidencia a la decisión” con el resumen de los juicios, la evidencia de investigación evaluada, consideraciones adicionales y comentarios planteados por el panel.

 1.- ¿El problema es una prioridad?
No Probablemente no Probablemente sí Varía No lo sé

El problema ha sido definido como prioritario en el marco de las Garantías Explícitas en Salud (GES), régimen integral de salud que prioriza un grupo de patologías o problemas de salud, garantizando el acceso a tratamiento oportuno y de calidad.

 2.- ¿Qué tan significativos son los efectos deseables anticipados?
Trivial Pequeño Moderado Grande Varía No lo sé

Esta pregunta fue evaluada en términos de seguridad de usar litio como monoterapia o usar antipsicóticos atípicos como monoterapia en mujeres embarazadas, por lo que no se emitieron juicios en base a efectos deseables.

 3.- ¿Qué tan significativos son los efectos indeseables anticipados?
Grande Moderado Pequeño Trivial Varía No lo sé

Pequeños: El equipo elaborador de la Guía estimó que los efectos indeseables de «usar litio como monoterapia» en comparación a «usar antipsicóticos atípicos como monoterapia» son pequeños, considerando la evidencia, experiencia clínica, conocimiento de gestión o experiencia de las personas con la condición o problema de salud.
En términos de seguridad, la evidencia sugiere que ambos fármacos tendrían efectos globales semejantes en cuanto a los desenlaces de desarrollo neurológico, malformaciones o problemas en el parto, cuando se usan en segundo o tercer trimestre. Estos resultados no son extrapolables al uso en el primer trimestre, donde incluso hay evidencia de aumento de malformaciones congénitas [13].
Si bien no están reportadas las consecuencias metabólicas del uso de estos fármacos, el equipo indica que, en la elección de tratamiento del segundo y tercer trimestre, se debe considerar los efectos metabólicos generados por los antipsicóticos atípicos y las comorbilidades de la mujer embarazada.

Evidencia de investigación

Tabla de Resumen de Resultados (Summary of Findings)

Litio comparado con antipsicóticos para embarazo.

 

Pacientes

Personas con trastorno bipolar en fase de mantención con embarazo en curso (segundo y tercer trimestre).

 

Intervención

Litio como monoterapia.

 

Comparación

Antipsicóticos atípicos como monoterapia.

 

Desenlaces

Efecto

Certeza de la evidencia

(GRADE)

Mensajes clave en términos sencillos

Desarrollo neurológico

Tres cohortes en una revisión [14] no encontraron diferencias en desarrollo neurológico al utilizar litio comparado con no usarlo.

Dos cohortes en una revisión [14] no encontraron diferencias en desarrollo neurológico al utilizar antipsicóticos atípicos comparado con no usarlo y 7 cohortes en una revisión [14] encontraron diferencias en diversos ámbitos como actividad motora, abstinencia, cognición, socio-emocional, conductual.

◯◯◯1,2,3

Muy baja

No está claro si litio comparado con antipsicóticos atípicos tiene diferencia en desarrollo neurológico en mujeres embarazadas.

Malforma-ciones

Un estudio de casos y controles [55] presenta un OR 2,62 (IC 95% 0,74 a 9,20) para malformaciones por uso de litio. 

 

A su vez una revisión sistemática reporta RR 1,0 (IC 95% 0,7 a 1,4) para olanzapina, RR 1,0 (IC 95% 0,6 a 1,7) para quetiapina, RR 1,5 (0,9 a 2,2) para risperidona y 1,4 (IC 95% 0,5 a 3,1) para aripiprazol.

◯◯◯1,2,3

Muy baja

No está claro si litio comparado con antipsicóticos atípicos tiene diferencia en malformaciones en mujeres embarazadas.

 

Problemas en el parto

Una cohorte de una revisión sistemática reportó una incidencia de 37% de partos prematuros en mujeres utilizando litio.

Una revisión sistemática [12] presenta un aumento de algunas complicaciones como posturas anormales, tono reducido y epilepsias. Sin embargo, estos corresponden a reportes de casos con el uso de clozapina. 

Otra revisión sistemática [6] reporta casos de taquicardia neonatal, insuficiencia respiratoria. Además, en un estudio de esta revisión [6] se reporta un aumento de parto prematuro con OR 2,57 (IC 95% 1,06 a 6,27) y retraso del crecimiento con OR  2,97 (IC 95% 1,23 a 7,16) utilizando aripiprazol.

◯◯◯1,2,3

Muy baja

No está claro si litio comparado con antipsicóticos atípicos tiene diferencia en problemas en el parto en mujeres embarazadas.

Complica-ciones metabólicas

No se identificaron revisiones sistemáticas que reporten acerca de complicaciones metabólicas del embarazo como diabetes gestacional o hipoglicemia del recién nacido.

 

IC 95%: Intervalo de confianza del 95% // RR: Riesgo relativo //
GRADE: Grados de evidencia Grading of Recommendations Assessment, Development and Evaluation.
1 Diseño observacional.
2 Se disminuyó un nivel de certeza de evidencia ya que la mayoría de los estudios presenta pérdidas importantes de pacientes y corresponden a estudios retrospectivos.
3 Se disminuyó un nivel de certeza de evidencia por inconsistencia ya que diferentes estudios presentan diferentes conclusiones.
4 Se disminuyó un nivel de certeza de evidencia por imprecisión ya que, si bien no hubo intervalo de confianza en muchas conclusiones, debido a la baja tasa de eventos es muy probable que el intervalo fuera muy amplio.
5 Se disminuyó dos niveles de certeza de evidencia por indirecto, ya que corresponde a una comparación indirecta sin metodología de network metanálisis, por lo cual las diferencias pueden explicarse por otras características en los estudios y no solamente por la intervención/comparación. Además, se decidió no disminuir certeza adicional pese a ser en otras enfermedades ya que el efecto adverso investigado principalmente es secundario uso en embarazo (Además, la gran mayoría de los estudios proviene de población bipolar).
Fecha de elaboración de la tabla: Enero, 2019.

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Búsqueda y Síntesis de Evidencia

 4.- ¿Cuál es la certeza general de la evidencia sobre efectos?
Muy baja Baja Moderada Alta Ningún estudio incluido

Muy Baja: Existe considerable incertidumbre respecto del efecto de «usar litio como monoterapia» en comparación a «usar antipsicóticos atípicos como monoterapia».

Evidencia de investigación

Desenlaces

Importancia

Certeza de la evidencia

(GRADE)

Desarrollo neurológico

CRÍTICA

⨁◯◯◯

MUY BAJAa,b,c,d

Malformaciones

CRÍTICA

⨁◯◯◯

MUY BAJAa,b,c

Problemas en el parto

CRÍTICA

⨁◯◯◯

MUY BAJAa,b,c,d

a. Se disminuyó un nivel de certeza de evidencia ya que la mayoría de los estudios presenta pérdidas importantes de pacientes y corresponden a estudios retrospectivos.
b. Se disminuyó un nivel de certeza de evidencia por inconsistencia ya que diferentes estudios presentan diferentes conclusiones.
c. Se disminuyó un nivel de certeza de evidencia por imprecisión ya que, si bien no hubo intervalo de confianza en muchas conclusiones, debido a la baja tasa de eventos es muy probable que el intervalo fuera muy amplio.
d. Se disminuyó dos niveles de certeza de evidencia por indirecto, ya que corresponde a una comparación indirecta sin metodología de network metanálisis, por lo cual las diferencias pueden explicarse por otras características en los estudios y no solamente por la intervención/comparación. Además, se decidió no disminuir certeza adicional pese a ser en otras enfermedades ya que el efecto adverso investigado principalmente es secundario uso en embarazo (Además, la gran mayoría de los estudios proviene de población bipolar).

 5.- ¿Hay incertidumbre importante o variabilidad sobre qué tanto valora la gente los desenlaces principales?
Incertidumbre o variabilidad importantes Posiblemente hay incertidumbre o variabilidad importantes Probablemente no hay incertidumbre ni variabilidad importantes No hay variabilidad o incertidumbre importante

Incertidumbre o variabilidad importantes: En función de la evidencia de investigación, experiencia clínica, conocimiento de gestión o experiencia de las personas con la condición o problema de salud, el equipo elaborador de la Guía consideró que existe incertidumbre o variabilidad importante respecto a lo que escogería una persona informada de los efectos deseables e indeseables de «usar litio como monoterapia» y «usar antipsicóticos atípicos como monoterapia».
De todos modos, el equipo indica que mujeres que opten por lactancia materna, probablemente escogerían por antipsicóticos atípicos. Otro factor a considerar en la decisión, es el fármaco de mantención utilizado de forma previa al embarazo.

Evidencia de investigación

No se encontró evidencia que diera cuenta de los valores o preferencias de personas con trastorno bipolar en fase de mantención con embarazo en curso (segundo y tercer trimestre), respecto a usar litio como monoterapia en comparación a usar antipsicóticos atípicos como monoterapia.

Referencias

1. Arvilommi P, Suominen K, Mantere O, Leppämäki S, Valtonen H, Isometsä E. Predictors of adherence to psychopharmacological and psychosocial treatment in bipolar I or II disorders – an 18-month prospective study. J Affect Disord [Internet]. 2014 Feb [cited 2018 Nov 26];155:110–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24262639

Búsqueda y Síntesis de Evidencia

 6.- El balance entre efectos deseables e indeseables favorece la intervención o la comparación?
Favorece la comparación Probablemente favorece la comparación No favorece la intervención ni la comparación Probablemente favorece la intervención Favorece la intervención Varía No lo sé

No favorece la intervención ni la comparación: Considerando que la intervención es «usar litio como monoterapia» y la comparación es «usar antipsicóticos atípicos como monoterapia», el equipo elaborador de la Guía opinó que la costo-efectividad no favorece ninguna de las dos alternativas.
Esto considerando que existe considerable incertidumbre respecto del efecto de «usar litio como monoterapia» en comparación a «usar antipsicóticos atípicos como monoterapia» y que habría incertidumbre o variabilidad importantes respecto a los escogerían las mujeres embarazadas.

 7.- ¿Qué tan grandes son los recursos necesarios (costos)?
Costos extensos Costos moderados Costos y ahorros despreciables Ahorros moderados Ahorros extensos Varía No lo sé

Costos y ahorros despreciables: El equipo elaborador de la Guía consideró que los costos y ahorros de «usar litio como monoterapia» son despreciables si se compara con «usar antipsicóticos atípicos como monoterapia», en función de los antecedentes, experiencia clínica, conocimiento de gestión o experiencia de los pacientes.

Evidencia de investigación

Tabla: Precios Referenciales
El porcentaje de cobertura del seguro de salud sobre el precio de las prestaciones sanitarias, dependerá del tipo de seguro de cada paciente.

Fármacos

Estabilizadores del ánimo antipsicóticos atípicos

Litio

Risperidona 3 mg – cm1

$32,3

Quetiapina 100 mg – cm1

$62,3

Olanzapina 10 mg – cm1

$84,1

Clozapina 100 mg – cm 1

$180,0

Aripiprazol 15 mg – cm1

$229,1

Litio carbonato 300 mg – cm1

$99,6

Rango de precio por comprimido

$32,3 a $229,1 

$ 99,60

Rango de precio mensual por un comprimido mensual

$969 a $6.872

$ 2.988,00

Referencias

1. Precio de compra por Establecimientos de Salud Públicos a través de plataforma Mercado Público, al 2018. Precio incluye IVA.

Búsqueda y Síntesis de Evidencia

 8.- ¿La costo-efectividad de la intervención beneficia la intervención o la comparación?
Favorece la comparación Probablemente favorece la comparación No favorece la intervención ni la comparación Probablemente favorece la intervención Favorece la intervención Varía Ningún estudio incluido

Ningún estudio incluido: No se encontraron estudios que respondieran la preguntan de interés.

Evidencia de investigación

No se realizó la búsqueda de estudios que abordaran la costo-efectividad de las intervenciones evaluadas ya que no son consideradas de alto costo (Anual $2.418.399 y Mensual $201.533), según lo establecido por el Ministerio de Salud en el “Decreto 80: Determinar umbral nacional de costo anual al que se refiere el artículo 6° de la Ley 20.850”.

 9.- ¿Cuál sería el impacto en equidad en salud?
Reducido Probablemente reducido Probablemente ningún impacto Probablemente aumentado Aumentado Varía No lo sé

Probablemente ningún impacto: El equipo elaborador de la Guía consideró que probablemente no tendría ningún impacto en la equidad en salud si se recomendase «usar litio como monoterapia», dado que estos fármacos se encuentran cubiertos por el Régimen de Garantías Explícitas de Salud.

 10.- ¿La intervención es aceptable para las partes interesadas?
No Probablemente no Probablemente sí Varía No lo sé

Varía: El equipo elaborador de la Guía considera que existen componentes que pueden afectar de distinta manera la aceptación de la intervención “usar litio como monoterapia» por las partes interesadas (profesionales de la salud, gestores de centros de salud, directivos servicios de salud, pacientes, cuidadores, seguros de salud, otros). Esta variación se debe principalmente por la paciente, en general, el uso de fármacos en el embarazo es rechazado por las pacientes y algunos clínicos.

 11.- ¿Es factible implementar la intervención?
No Probablemente no Probablemente sí Varía No lo sé

Sí: El equipo elaborador de la Guía consideró que «usar litio como monoterapia» SÍ es factible implementar, contemplando que estos fármacos se encuentran cubiertos por el Régimen de Garantías Explícitas de Salud.