Expansores del plasma para personas con cirrosis y ascitis de gran volumen tratadas con paracentesis abdominal
Resumen
Antecedentes
Los expansores del volumen plasmático se utilizan en relación con la paracentesis en personas con cirrosis para prevenir la reducción del volumen plasmático efectivo, que puede desencadenar un efecto perjudicial sobre el equilibrio hemodinámico y aumentar la morbimortalidad. La albúmina se considera el producto estándar con el cual no se han comparado ninguna expansión del plasma ni otros expansores del plasma , por ejemplo otros coloides (dextrano, poligelina, solución de hidroxietilalmidón, plasma fresco congelado), infusión intravenosa de líquido ascítico, cristaloides o manitol. Sin embargo, no se conocen del todo los efectos beneficiosos y perjudiciales de estos expansores del plasma.
Objetivos
Evaluar los efectos beneficiosos y perjudiciales de cualquier expansor del volumen plasmático como la albúmina, otros coloides (dextrano, poligelina, solución de hidroxietilalmidón, plasma fresco congelado), infusión intravenosa de líquido ascítico, cristaloides o manitol versus ningún expansor del volumen plasmático o versus otro expansor del volumen plasmático para la paracentesis en personas con cirrosis y ascitis de gran volumen.
Métodos de búsqueda
Se hicieron búsquedas en el registro de ensayos controlados del Grupo Cochrane Hepatobiliar (Cochrane Hepato‐Biliary Group), en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials; CENTRAL), MEDLINE, Embase, LILACS, CNKI, VIP, Wanfang, Science Citation Index Expanded y en el Conference Proceedings Citation Index hasta enero de 2019. Además, se realizaron búsquedas en la FDA, EMA y OMS (última búsqueda enero de 2019), www.clinicaltrials.gov/, y www.controlled‐trials.com/ .
Criterios de selección
Ensayos clínicos aleatorizados, sin importar su diseño, idioma, año o estado de publicación, que evaluaron el uso de cualquier tipo de expansor del plasma versus placebo, ninguna intervención u otro expansor del plasma en relación con la paracentesis para la ascitis en personas con cirrosis. Se consideraron ensayos cuasialeatorizados identificados mediante las búsquedas exclusivas de ensayos clínicos aleatorizados,para la información sobre los daños.
Obtención y análisis de los datos
Se utilizaron los procedimientos metodológicos estándar previstos por Cochrane. Se calculó el cociente de riesgos (CR) o la diferencia de medias (DM) usando metanálisis de modelo de efectos fijos y de modelo de efectos aleatorios, sobre la base del principio de intención de tratar, siempre que fue posible. Si los modelos de efectos fijos y de efectos aleatorios mostraron resultados diferentes, se establecieron las conclusiones con base en el análisis con el mayor valor de p (el resultado más conservador). El riesgo de sesgo de los ensayos individuales se evaluó mediante dominios predeterminados del riesgo de sesgo. La certeza general de la evidencia a nivel de resultado se evaluó mediante GRADE y se crearon dos tablas de "Resumen de los hallazgos" para siete de los resultados de la revisión.
Resultados principales
Se identificaron 27 ensayos clínicos aleatorizados para su inclusión en esta revisión (24 publicados como artículos completos y 3 como resúmenes). Cinco ensayos, con 271 participantes, evaluaron los expansores del plasma (albúmina en cuatro ensayos y líquido ascítico en uno) versus ningún expansor del plasma. Los 22 ensayos restantes, con 1321 participantes, evaluaron un tipo de expansor del plasma, es decir, dextrano, poligelina, hidroxietilalmidón, infusión intravenosa de líquido ascítico, cristaloides o manitol versus otro tipo de expansor del plasma, es decir, albúmina en 20 de los ensayos y poligelina en uno. Veinticinco ensayos proporcionaron datos del metanálisis cuantitativo. Según la clasificación Child‐Pugh, la mayoría de los participantes estaban en un estadio intermedio a avanzado de la enfermedad hepática en ausencia de carcinoma hepatocelular, hemorragia gastrointestinal reciente, infecciones y encefalopatía hepática. Todos los ensayos tuvieron un riesgo de sesgo alto en general. Diez ensayos no parecían haber sido financiados por la industria; doce ensayos se consideraron poco claros acerca de la financiación y cinco ensayos se consideraron financiados por la industria o una institución con ánimo de lucro.
No se halló evidencia de una diferencia en el efecto entre la expansión del plasma versus ninguna expansión del plasma en la mortalidad (CR 0,52, IC del 95%: 0,06 a 4,83; 248 participantes; 4 ensayos; certeza muy baja), insuficiencia renal (CR 0,32, IC del 95%: 0,02 a 5,88; 181 participantes; 4 ensayos; certeza muy baja), otras complicaciones hepáticas (CR 1,61, IC del 95%: 0,79 a 3,27; 248 participantes; 4 ensayos; certeza muy baja) y eventos adversos no graves (CR 1,04, IC del 95%: 0,32 a 3,40; 158 participantes; 3 ensayos; certeza muy baja). Dos de los ensayos informaron que no se produjeron eventos adversos graves y el resto de ensayos no informaron este resultado. Ningún ensayo informó datos sobre la calidad de vida relacionada con la salud.
No se halló evidencia de una diferencia en el efecto entre los expansores del plasma experimentales versus albúmina en la mortalidad (CR 1,03, IC del 95%: 0,82 a 1,30; 1014 participantes; 14 ensayos; certeza muy baja), eventos adversos graves (CR 0,89, IC del 95%: 0,10 a 8,30; 118 participantes; 2 ensayos; certeza muy baja), insuficiencia renal (CR 1,17, IC del 95%: 0,71 a 1,91; 1107 participantes; 17 ensayos; certeza muy baja), otras complicaciones hepáticas (CR 1,10, IC del 95%: 0,82 a 1,48; 1083 participantes; 16 ensayos; certeza muy baja) y eventos adversos no graves (CR 1,37, IC del 95%: 0,66 a 2,85; 977 participantes; 14 ensayos; certeza muy baja). No se encontraron datos de la calidad de vida relacionada con la salud ni de la ascitis refractaria.
Conclusiones de los autores
La revisión sistemática y el metanálisis no pudieron hallar ningún beneficio ni daño de los expansores del plasma versus ningún expansor o de un expansor del plasma, como poligelina, dextrano, hidroxietilalmidón, plasma fresco congelado, infusión intravenosa de líquido ascítico, cristaloides o manitol versus albúmina en los resultados primarios ni secundarios. Los datos provenían de tan solo unos pocos ensayos pequeños y mayoritariamente a corto plazo, con un riesgo alto de errores sistemáticos (sesgo) y con un alto riesgo de errores aleatorios (intervención del azar). Las evaluaciones mediante el método GRADE concluyeron que la evidencia fue de certeza muy baja. Por lo tanto, no se puede mostrar ni descartar ningún beneficio de la expansión del plasma versus ninguna expansión del plasma, ni las diferencias entre un expansor del plasma y otro.
Se necesitan ensayos más grandes y con bajo riesgo de sesgo para evaluar el papel de los expansores del plasma en relación con la paracentesis. Tales ensayos se deberían realizar según las directrices SPIRIT e informar según las directrices CONSORT.
PICO
Resumen en términos sencillos
Expansores del plasma para personas con cirrosis y ascitis de gran volumen tratadas con paracentesis abdominal
Antecedentes
Las personas con cirrosis (cicatrización del tejido hepático) pueden acumular líquido (ascitis) en el abdomen, lo cual puede ser difícil o imposible de tratar con diuréticos (medicamentos que aumentan la excreción urinaria de agua y sal). Se puede realizar una paracentesis abdominal, es decir, la evacuación del líquido del abdomen a través de una aguja. La paracentesis puede alterar el equilibrio entre la circulación y el líquido abdominal y provocar disfunción renal y alteración del balance hídrico. Se estudió si la infusión de líquidos especiales, los llamados expansores del plasma, podían detener estas alteraciones y reducir las complicaciones y la mortalidad.
Objetivo
Evaluar los beneficios y los daños de cualquier infusión intravenosa de líquido (que actúa como expansión del plasma) en personas con cirrosis y ascitis tratadas por paracentesis.
Métodos y criterios de la revisión
Las pruebas están actualizadas hasta el 22 de enero de 2019.
Esta revisión sistemática evaluó la función de los expansores del plasma evaluados en 27 ensayos con 1592 participantes. Cuatro ensayos compararon la albúmina y un ensayo comparó la infusión intravenosa de líquido ascítico versus ningún expansor del plasma. Veintiún ensayos compararon un expansor del plasma como dextrano, poligelina, hidroxietilalmidón, plasma fresco congelado, infusión intravenosa de líquido ascítico, cristaloides o manitol versus albúmina. Un ensayo comparó la infusión intravenosa de líquido ascítico versus poligelina. Los resultados primarios fueron: la mortalidad por cualquier causa, los eventos adversos graves y la calidad de vida relacionada con la salud. Las medidas de resultado secundarias fueron ascitis refractaria (ascitis que no pudo ser tratada médicamente); insuficiencia renal; otras complicaciones debidas a cirrosis hepática como hemorragia gastrointestinal, encefalopatía hepática (disminución de la función cerebral debido a enfermedad hepática) o infecciones; y eventos adversos no graves.
Fuentes de financiación de los ensayos
Diez ensayos no parecían haber sido financiados por la industria; doce ensayos se consideraron poco claros acerca de la financiación y cinco ensayos se consideraron financiados por la industria o una institución con ánimo de lucro.
Resultados clave
La revisión sistemática no pudo mostrar ningún beneficio ni daño de los expansores versus ningún expansor del plasma o de un expansor como dextrano, poligelina, hidroxietilalmidón, plasma fresco congelado, infusión intravenosa de líquido ascítico, cristaloides o manitol versus albúmina en los resultados primarios o secundarios.
Certeza de la evidencia
Los datos provenían de tan solo unos pocos ensayos pequeños y mayoritariamente a corto plazo, con un riesgo alto de errores sistemáticos (sesgo) y con un alto riesgo de errores aleatorios (intervención del azar). Por lo tanto, se concluyó que la certeza de la evidencia fue muy baja para cada uno de los resultados preespecificados de la revisión.
Conclusiones de los autores
Summary of findings
| Plasma expanders versus no plasma expanders for people with cirrhosis and large ascites treated with abdominal paracentesis: primary and secondary outcomes | ||||||
| Patient or population: cirrhotic participants with large ascites treated by paracentesis Settings: specialised units in an intensive or semi‐intensive setting Intervention: plasma expander Comparison: no plasma expander | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No plasma expander | Plasma expander | |||||
| All‐cause mortality mean follow‐up 64 days (1‐222) | Medium risk population | RR 0.52 (0.06 to 4.83) | 248 | ⊕⊝⊝⊝ | ||
| 180 per 1000 | 94 per 1000 | |||||
| Serious adverse events mean follow‐up 15 days (1‐30) | See comment | See comment | See comment | 108 | ⊕⊝⊝⊝ | Two trials reported that no serious adverse events occurred |
| Health‐related quality of life | No data provided in any of the six trials | |||||
| Refractory ascites | No data provided in any of the six trials | |||||
| Other liver‐related complications mean follow‐up 64 days (1‐222) | Medium risk population | RR 1.61 (0.79 to 3.27) | 248 | ⊕⊝⊝⊝ | ||
| 90 per 1000 | 145 per 1000 | |||||
| Non‐serious adverse events mean follow‐up 91 days (1‐222) | Medium risk population | RR 1.04 (0.32 to 3.4) | 158 | ⊕⊝⊝⊝ | ||
| 62 per 1000 | 64 per 1000 | |||||
| * Assumed risk is the risk in comparison group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded 4 levels because of within study risk of bias: all trials were at high risk of bias (‐2 levels); heterogeneity: high heterogeneity (76%) (‐1 level); imprecision: the required information size as calculated by GRADE was not reached (‐1 level) | ||||||
| Other plasma expanders versus albumin for people with cirrhosis and large ascites treated with abdominal paracentesis: primary and secondary outcomes | ||||||
| Patient or population: cirrhotic participants with large ascites treated by paracentesis Settings: specialised units in an intensive or semi‐intensive setting Intervention: all plasma expanders except albumin Comparison: albumin | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Certainty of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Albumin | Experimental plasma expanders | |||||
| All‐cause mortality mean follow‐up 208 days (3‐638) | Medium risk population | RR 1.03 (0.82 to 1.30) | 1014 | ⊕⊝⊝⊝ very low 1 | ||
| 183 per 1000 | 188 per 1000 | |||||
| Serious adverse events mean follow‐up 93 days (6‐180) | Medium risk population | RR 0.89 (0.10 to 8.30) | 118 | ⊕⊝⊝⊝ very low 2 | ||
| 18 per 1000 | 16 per 1000 | |||||
| Health‐related quality of life | No data provided in any of the 20 trials | |||||
| Refractory ascites | No data provided in any of the 20 trials | |||||
| Renal impairment mean follow‐up 174 days (3‐628) | Medium risk population | RR 1.17 (0.71 to 1.91) | 1107 | ⊕⊝⊝⊝ | ||
| 49 per 1000 | 57 per 1000 | |||||
| Other liver‐related complications mean follow‐up 147 days (3‐638) | Medium risk population | RR 1.10 (0.82 to 1.48) | 1083 | ⊕⊝⊝⊝ | ||
| 185 per 1000 | 203 per 1000 | |||||
| Non‐serious adverse events mean follow‐up 194 days (3‐638) | Medium risk population | RR 1.37 (0.66 to 2.85) | 977 (14) | ⊕⊝⊝⊝ | ||
| 25 per 1000 | 34 per 1000 | |||||
| * Assumed risk is the risk in comparison group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded 4 levels because of within study risk of bias: all trials were at high risk of bias (‐2 levels); imprecision: the required information size as calculated by GRADE was not reached (‐1 level); publication bias (‐1 level) | ||||||
Antecedentes
Descripción de la afección
La ascitis se asocia con una mayor mortalidad en los pacientes con cirrosis (D'Amico 1986; Salerno 1991; D'Amico 2006). La ascitis se clasifica como leve, moderada y de gran volumen o severa (AASLD 2009; AASLD 2012; EASL 2018). Se ha mostrado que las personas con asicitis leve a moderada responden de forma positiva a la restricción de sodio alimentario y a los diuréticos (Runyon 1998; AASLD 2009; AASLD 2012; EASL 2018). No obstante, las personas con ascitis de gran volumen podrían tener problemas respiratorios, en cuyo caso la paracentesis se suele emplear para proporcionar alivio (Ginés 1987). La paracentesis puede ser parcial, definida como sesiones repetidas de paracentesis; o total, cuando se realiza en una única sesión (Titó 1990). La paracentesis abdominal parece asociarse con una menor incidencia de eventos adversos y una más rápida resolución en comparación con el tratamiento diurético (Ginés 1987). Además, la paracentesis repetida se utiliza en personas con ascitis de gran volumen que no responden al tratamiento diurético intensivo y a la restricción de sodio alimentario, o a aquellas que experimentan efectos adversos de estos tratamientos (p. ej.: hipotensión, hiponatremia, hiperpotasemia, insuficiencia renal o encefalopatía hepática). Este tipo de ascitis se define como refractaria (Arroyo 1996; Runyon 1998; Moore 2003; AASLD 2009; AASLD 2012; EASL 2018).
La paracentesis podría inducir hipovolemia y alteraciones hemodinámicas con disfunción circulatoria que se expresa por un marcado aumento de la actividad de la renina plasmática en un 27% a 40% de personas sometidas a paracentesis, como informan Ruiz‐del‐Arbol 1997 y Vila 1998. Este síndrome, denominado disfunción circulatoria posparacentesis (o disfunción circulatoria inducida por paracentesis) podría estar asociado con un menor tiempo hasta el reingreso y supervivencia más corta (Ginès 1996), pero no está claro si su prevención reduciría la morbimortalidad.
Descripción de la intervención
La infusión intravenosa de líquidos, como expansor del plasma, podría contrarrestar los efectos nocivos de la paracentesis.
Los resultados de estudios hemodinámicos (García‐Compeán 1993; Luca 1995) y clínicos (Ginès 1988; Ginès 1996) sugieren que el riesgo de hipovolemia y disfunción circulatoria podría reducirse con la infusión intravenosa de albúmina. Puesto que la albúmina es cara, la expansión del volumen también se realiza administrando coloides más económicos (dextrano, poligelina, solución de hidroxietilalmidón, plasma fresco congelado), cristaloides, manitol o mediante infusión intravenosa del líquido ascítico retirado. Los efectos de estas intervenciones se han comparado con los de la albúmina en ensayos clínicos aleatorizados, pero los resultados han sido heterogéneos (Planas 1990; Smart 1990; Salerno 1991; Bruno 1992; Fassio 1992; Ginès 1996; Moreau 2006; Al Sebaey 2012).
De qué manera podría funcionar la intervención
La paracentesis puede aumentar la vasodilatación arterial en personas con ascitis cirrótica, lo cual podría reducir el volumen plasmático circulatorio efectivo y dar lugar a una reducción de la presión arterial y la activación del sistema renina‐angiotensina‐aldosterona (SRAA) y del sistema nervioso simpático. Esto, a su vez, puede producir una mayor retención de sodio y agua y a la vasoconstricción renal (Ruiz‐del‐Arbol 1997; Saló 1997; Vila 1998).
La expansión plasmática podría prevenir o mejorar el desajuste hemodinámico inducido por la paracentesis, rellenando el sistema vascular y equilibrando el descenso de la resistencia vascular (previniendo así la posterior activación de los sistemas vasoconstrictores) (Ginès 1988). El uso de la albúmina se basa en su efecto sobre el volumen intravascular y también en sus propiedades antiinflamatorias y vasoconstrictoras (Garcia‐Martinez 2013; Garcia‐Tsao 2018).
Por qué es importante realizar esta revisión
Durante mucho tiempo se han cuestionado los beneficios de la albúmina y otros coloides. Se han realizado muchos ensayos clínicos aleatorizados para evaluar el papel de la albúmina o los coloides en el contexto de cuidados intensivos y se han publicado varias revisiones sistemáticas Cochrane sobre este tema (Cochrane Injuries Group Albumin Reviewers 1998; Schierhout 1998a; Alderson 2002; Roberts 2011; Perel 2013; Lewis 2018). En la revisión Cochrane de Perel y colegas, no se halló ningún beneficio para los coloides, incluida la albúmina, en comparación con cristaloides para la reanimación con líquidos en pacientes críticos con traumatismo, quemaduras o después de una cirugía. Sin embargo, la revisión halló evidencia de un aumento de la mortalidad debido a la administración de hidroxietilalmidón (Perel 2013). Estos resultados no son consistentes con los de otras dos revisiones sistemáticas (He 2015; Qureshi 2016). Más recientemente, Lewis y colegas actualizaron la revisión de Perel 2013, y excluyeron a los participantes con cirugía programada. Los autores de la revisión confirmaron que es probable que los coloides en comparación con cristaloides para el reemplazo de líquidos logren poco o ningún cambio en la mortalidad de pacientes en estado crítico. Los autores de la revisión tampoco hallaron un aumento de la mortalidad debido a las soluciones de hidroxietilalmidón (Lewis 2018). El hidroxietilalmidón parece aumentar la mortalidad en personas con sepsis grave, según los estudios de Haase 2013, Haase 2014, y Perner 2014. Estos resultados continúan suscitando el debate, sobre todo en el uso de albúmina y otros expansores del plasma en pacientes en cuidados intensivos (Bapat 1998; Beale 1998; Chalmers 1998; Corder 1998; Frame 1998; Goodman 1998; Gosling 1998; Kaag 1998; Lawler 1998; Makin 1998; McAnulty 1998; Nadel 1998; Nel 1998; Offringa 1998; Petros 1998; Riordan 1998; Roberts 1998; Schierhout 1998b; Shwe 1998; Soni 1998; Watts 1998; Wyncoll 1998; Roberts 1999; Hartog 2014; Haase 2014).
En pacientes con cirrosis, la albúmina se ha utilizado con diferentes resultados en relación con la paracentesis (Ginés 1987; Ginès 1988; Titó 1990), o con diuréticos (Gentilini 1999; Romanelli 2006), en personas con peritonitis bacteriana espontánea, otras infecciones bacterianas (Sort 1999; Guevara 2012; Kwok 2013; Salerno 2013; Thévenot 2015), en pacientes con síndrome hepatorrenal con o sin el uso de vasoconstrictores (Martín‐Llahí 2008; Boyer 2016) o en pacientes con hiponatremia (McCormick 1990; Jalan 2007; Bajaj 2018). Recientemente, se observó un aumento de la supervivencia con la administración de albúmina a largo plazo en un ensayo aleatorizado abierto de gran tamaño que incluyó participantes con cirrosis descompensada y ascitis no complicada tratados con diuréticos (Caraceni 2018) y en un estudio no aleatorizado que incluyó participantes con ascitis refractaria (Di Pascoli 2019). Por el contrario, en participantes con cirrosis a la espera de un trasplante hepático, el tratamiento con albúmina y midodrina no previno complicaciones de la cirrosis ni mejoró la supervivencia (O’Brien 2018; Solà 2018). Recientemente se han publicado opiniones contradictorias acerca del uso de la albúmina en este contexto específico de pacientes (Bernardi 2019; O'Brien 2019).
Un metanálisis de ensayos clínicos aleatorizados de albúmina para una serie de indicaciones, incluido el tratamiento de personas con cirrosis y ascitis tensa (probablemente comparable a la ascitis de gran volumen), no mostró efecto alguno sobre la mortalidad (Wilkes 2001). A este le han seguido otros metanálisis que incluyeron solo a personas con cirrosis y ascitis de gran volumen (Wong 2008; Bernardi 2012; Wang 2015). En el metanálisis de Bernardi y colegas en personas tratadas con paracentesis, la albúmina versus ningún tratamiento redujo la disfunción circulatoria posparacentesis y la hiponatremia, y la albúmina versus tratamientos alternativos (otros expansores del plasma y vasoconstrictores) redujo la disfunción circulatoria posparacentesis, la hiponatremia y la mortalidad. No hubo reducción de otras complicaciones (Bernardi 2012).. Se obtuvieron resultados similares en el metanálisis de Wang y colegas, en el cual la albúmina se comparó con otros expansores del plasma y con vasoconstrictores (Wang 2015). Wong y colegas informaron datos sobre la paracentesis realizada con o son albúmina, u otro expansor del plasma, y no observaron ningún efecto consistente sobre la morbimortalidad entre las intervenciones (Wong 2008). El último metanálisis, publicado por Kütting y colegas, concluyó que no había evidencia suficiente de un beneficio respecto a la mortalidad a causa de la sustitución con albúmina en los participantes cirróticos sin cáncer hepatocelular que recibieron un elevado volumen de paracentesis (Kütting 2017).
A pesar de las conclusiones contradictorias de estas revisiones sistemáticas, la expansión del plasma con albúmina tras una paracentesis de gran volumen está recomendada en varias guías (AASLD 2012; AISF 2016; EASL 2018) en las cuales un elevado número de recomendaciones hacen referencia al metanálisis de Bernardi 2012.
La revisión sistemática actual no evaluará los efectos beneficiosos y perjudiciales de la administración a largo plazo de expansores del plasma en pacientes con cirrosis ni en personas con peritonitis bacteriana espontánea o síndrome hepatorrenal, ni cuando estos se utilizan después de una paracentesis en comparación con diuréticos o una derivación portosistémica intrahepática transyugular (TIPS). Los objetivos se describen a continuación.
Objetivos
Evaluar los efectos beneficiosos y perjudiciales de cualquier expansor del volumen plasmático como la albúmina, otros coloides, infusión intravenosa de líquido ascítico, cristaloides o manitol versus ningún expansor del volumen plasmático o versus otro expansor del volumen plasmático para la paracentesis en personas con cirrosis y ascitis de gran volumen.
Métodos
Criterios de inclusión de estudios para esta revisión
Tipos de estudios
Ensayos clínicos aleatorizados que examinaron expansores del plasma administrados en relación con la paracentesis en personas con cirrosis y ascitis de gran volumen. Los ensayos podían estar publicados o no, como un artículo completo, un resumen o un póster. Se incluyeron ensayos independientemente del cegamiento, el idioma, y la fecha de publicación. Se consideraron estudios cuasialeatorizados identificados mediante las búsquedas de ensayos clínicos aleatorizados, para la información sobre los efectos perjudiciales solo, puesto que es poco frecuente que los eventos adversos se capturen en los ensayos clínicos aleatorizados (Storebø 2018). Los autores son conscientes de que con estos métodos de selección se pone más énfasis en los beneficios que en los efectos perjudiciales de estas intervenciones.
Tipos de participantes
Adultos con cirrosis y ascitis de gran volumen, tanto si esta responde a los diuréticos como si es refractaria. El diagnóstico de la cirrosis se podía establecer mediante datos clínicos y de laboratorio o histología hepática. Se excluyeron ensayos que incluyeran a personas con peritonitis bacteriana espontánea, insuficiencia hepática crónica en fase aguda o carcinoma hepatocelular, o a personas con tratamiento quirúrgico o paraquirúrgico anteriores (anastomosis quirúrgica de la vena cava, trasplante hepático y derivación portosistémica intrahepática transyugular).
La ascitis se define como refractaria si no puede ser movilizada o si la recurrencia temprana de la misma no puede prevenirse debido a una falta de respuesta a la restricción de sodio y el tratamiento diurético (ascitis resistente a diuréticos), o por la aparición de complicaciones inducidas por los diuréticos (p. ej.: hipotensión, encefalopatía hepática, insuficiencia renal funcional, hiponatremia, etc.) que impidieran el uso de una posología diurética efectiva (ascitis no tratable con diuréticos) (Arroyo 1996; Moore 2003). Se registró la definición de ascitis refractaria utilizada en los ensayos si difería de la definición anterior (Arroyo 1996; Moore 2003). Se etiquetaron como “ensayos sin ascitis refractaria” aquellos en los que los participantes con ascitis refractaria fueron excluidos o, si no se indicaba claramente, aquellos ensayos en los que el tratamiento diurético se había informado hasta el ingreso hospitalario y las concentraciones medias de urea, creatinina y sodio en sangre fueron normales, puesto que se esperaba que la proporción de ascitis refractaria fuera baja, en caso de haberla.
Tipos de intervenciones
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Expansión del volumen plasmático mediante albúmina, otros coloides, infusión intravenosa de líquido ascítico, cristaloides o manitol versus ningún expansor del volumen plasmático (es decir, placebo o ninguna intervención), administrados en relación con la paracentesis.
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Expansión del volumen plasmático mediante un expansor del volumen plasmático versus otro expansor del volumen plasmático, administrados en relación con la paracentesis.
Se incluyeron ensayos clínicos aleatorizados con intervenciones colaterales si se utilizaron de la misma manera en los grupos de comparación del ensayo.
Tipos de medida de resultado
Resultados primarios
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Mortalidad por todas las causas al final del seguimiento máximo.
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Eventos adversos graves al final del seguimiento máximo, excluyendo aquellos para los cuales podía aplicar la definición de otras complicaciones relacionadas con el hígado (ver a continuación). Se consideró que un evento era un evento adverso grave si cumplía la definición de evento adverso grave de acuerdo con las pautas del International Conference on Harmonization Guidelines (ICH) (ICH 1997), es decir, cualquier evento que produzca la muerte, ponga en riesgo la vida, requiera la hospitalización del paciente o la prolongación de la hospitalización actual, lleve a discapacidad persistente o significativa, anomalía congénita y cualquier evento médico importante que pueda poner en peligro al paciente o requiera intervención para prevenirlo. Todos los otros eventos adversos se consideraron no graves.
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Calidad de vida relacionada con la salud medida por los ensayos.
Resultados secundarios
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Ascitis refractaria (ver la definición más arriba).
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Insuficiencia renal.
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Otras complicaciones debido a la cirrosis hepática como, hemorragia gastrointestinal, encefalopatía hepática o infecciones (definidas aquí como “otras complicaciones relacionadas con el hígado”). Este resultado no incluyó las medidas de resultado enumeradas como resultados exploratorios.
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Eventos adversos no graves.
Resultados exploratorios
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Recurrencia de ascitis, definida como ascitis que requiere paracentesis repetida u hospitalización, o ambas.
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Hipotensión según la definieron los autores del ensayo.
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Hiponatraemia según la definieron los autores de los ensayos.
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Disfunción circulatoria posparacentesis, definida como un aumento de la actividad de renina plasmática de más del 50% del valor anterior al tratamiento a un nivel de más de 4 ng/ml/h en el sexto día posterior a la paracentesis (Ginès 1996).
Métodos de búsqueda para la identificación de los estudios
Búsquedas electrónicas
We identified relevant studies by searching the Cochrane Hepato‐Biliary Group Controlled Trials Register (January 2019), the Cochrane Central Register of Controlled Trials (CENTRAL in the Cochrane Library, Issue 1, 2019), MEDLINE (1946 to January 2019), Embase (1974 to January 2019), LILACS (1982 to January 2019), three Chinese database including CNKI, VIP, and Wanfang (to August 2015), Science Citation Index Expanded (1900 to January 2019), and Conference Proceedings Citation Index (1990 to January 2019).
We also searched databases of ongoing trials (www.clinicaltrials.gov/ and www.controlled‐trials.com/) (with links to several databases). In addition, we searched the European Medicines Agency (EMA, www.ema.europe.eu), US Food and Drug Administration (FDA, www.fda.gov), and the World Health Organization International Clinical Trials Registry Platform (ICTRP 2011) until January 2019. For detailed search strategies, see Appendix 1. We did not apply any language or document type restrictions. We contacted authors of the included trials to request missing information.
Búsqueda de otros recursos
We checked references of included trials, meta‐analyses, and other publications that were retrieved with the searches for randomised clinical trials in order to identify further trials of relevance to our review.
Obtención y análisis de los datos
We performed the systematic review and meta‐analyses following recommendations of Cochrane (Higgins 2011), and the Cochrane Hepato‐Biliary Group (Gluud 2015). In the case of cross‐over trials, we included data only from the first period (Higgins 2011). We performed the analyses using Review Manager 5.3 (RevMan 2014) and Trial Sequential Analysis version 0.9 (Wetterslev 2008; Thorlund 2011; TSA 2011). We assessed the evidence according to recommendations from Jakobsen and colleagues (Jakobsen 2014).
Selección de los estudios
Two of the authors, RGS and GP, independently of each other, identified the trials for inclusion in accordance with the inclusion criteria of the updated review protocol and listed the excluded studies with the reasons for their exclusion. RGS and GP resolved disagreements through discussions.
Extracción y manejo de los datos
Two authors, RGS and GP, independently extracted data. We resolved disagreements by discussion. Data extraction encompassed:
‐ trial inclusion and exclusion criteria;
‐ the comparability between the groups randomised to alternative treatments regarding baseline prognostic variables: aetiology of cirrhosis; mean age; proportion of males/females; participants with Child‐Pugh stages A, B, or C (Pugh 1973); proportion of participants with hepatic encephalopathy, with previous gastrointestinal bleeding episodes, with type of ascites (that is, large ascites: either diuretic‐responsive, or refractory ascites), or with arterial hypotension; mean arterial pressure; renal impairment; hyponatraemia. Furthermore, we recorded plasma renin activity, plasma aldosterone levels, urinary sodium excretion, and information on liver biochemistry (serum bilirubin, albumin, and prothrombin time or international normalised ratio);
‐ treatments during the trial: type and dose of plasma expander, and timing of administration of plasma expander in connection to paracentesis; for intravenous infusion of ascitic fluid, whether or not the ascitic fluid was filtered and concentrated; type of paracentesis (partial or total paracentesis); total amount of ascitic fluid removed; length of the procedure; sodium restriction and diuretics (type and dose) before and after paracentesis; timing for clinical and laboratory assessment;
‐ sample size calculation performed and reported;
‐ completeness and length of follow‐up of treatment groups and reasons for withdrawals;
‐ presence of, absence of or unknown for‐profit support.
Evaluación del riesgo de sesgo de los estudios incluidos
Due to the risk of overestimation of beneficial intervention effects and underestimation of harmful intervention effects in randomised clinical trials at unclear risk of bias or at high risk of bias (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Savović 2012a; Savović 2012b), we assessed the influence of the risk of bias on our results. We used the domains with definitions provided below to assess the risk of bias in the included trials (Higgins 2011; Gluud 2015).
Allocation sequence generation
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Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice are adequate if performed by an independent research assistant not otherwise involved in the trial.
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Unclear risk of bias: the method of sequence generation was not specified.
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High risk of bias: the sequence generation method was not random.
Allocation concealment
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Low risk of bias: the participant allocations could not have been foreseen in advance of, or during enrolment. Allocation was controlled by a central and independent randomisation unit. The allocation sequence was unknown to the investigators (for example, if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).
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Unclear risk of bias: the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during enrolment.
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High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants.
Blinding of participants and personnel
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Low risk of bias: any of the following: no blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; or blinding of participants and key study personnel ensured, and it is unlikely that the blinding could have been broken.
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Unclear risk of bias: any of the following: insufficient information to permit judgement of ‘low risk’ or ‘high risk’; or the trial did not address this outcome.
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High risk of bias: any of the following: no blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; or blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
Blinding of outcome assessment
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Low risk of bias: any of the following: no blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; or blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
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Unclear risk of bias: any of the following: insufficient information to permit judgement of ‘low risk’ or ‘high risk’; or the trial did not address this outcome.
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High risk of bias: any of the following: no blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; or blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
Incomplete outcome data
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Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. The study used sufficient methods, such as multiple imputation, to handle missing data.
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Unclear risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.
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High risk of bias: the results were likely to be biased due to missing data.
Selective outcome reporting
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Low risk of bias: the trial reported the following predefined outcomes: all‐cause mortality, serious adverse events, refractory ascites, renal impairment, other complications due to liver cirrhosis such as gastrointestinal bleeding, hepatic encephalopathy, or infections, and non‐serious adverse events. If the original protocol was available, the outcomes should be those called for in that protocol. If the trial protocol was obtained from a trial registry (e.g. www.clinicaltrials.gov), the outcomes sought should have been those enumerated in the original protocol if the trial protocol was registered before or at the time when the trial was begun. If the trial protocol was registered after the trial was begun, those outcomes were not considered to be reliable.
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Unclear risk of bias: the study authors did not report all predefined outcomes fully, or it was not clear whether data on this outcomes were recorded or not.
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High risk of bias: the study authors did not report all‐cause mortality or more secondary predefined outcomes.
Other bias
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Low risk of bias: the trial appeared to be free of other bias domains that could put it at risk of bias.
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Unclear risk of bias: the trial might or might not have been free of other domains that could have put it at risk of bias.
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High risk of bias: there are other factors in the trial that could put it at risk of bias.
RGS and GP judged a trial to be at an overall low risk of bias when the trial was assessed as having a low risk of bias in all the above domains. RGS and GP judged a trial to be at an overall high risk of bias when the trial was assessed as having an unclear risk of bias or a high a risk of bias in one or more of the above domains.
RGS and GP resolved disagreements by discussion.
Medidas del efecto del tratamiento
Dichotomous outcomes
We used the risk ratio (RR) with 95% CI. We used both fixed‐effect and random‐effects meta‐analysis models.
Continuous outcomes
We planned to use the mean difference (MD) with 95% CI or the standard mean difference (SMD) with 95% CI, depending on whether the scales used in the trials were the same or different.
Cuestiones relativas a la unidad de análisis
The participants as randomised to the intervention groups of the clinical trials. In trials with a two parallel group design, we compared the experimental intervention group versus the control group. In the trials with a parallel group design with more than two intervention groups, we compared separately each of the experimental groups with the control group divided proportionately according to number of experimental groups.
In cross‐over trials, we only included the data from the first trial period in order avoid residual effects from the treatment (Higgins 2011). In order to avoid repeated observations on trial participants, we used participant trial data at the longest follow‐up (Higgins 2011).
Manejo de los datos faltantes
We tried to obtain missing data from authors of the included trials. We investigated attrition bias (i.e. dropouts, losses to follow‐up, and withdrawals). We performed our analyses based on the intention‐to‐treat principle, whenever possible.
Regarding the primary outcomes, we included participants with incomplete or missing data in sensitivity analyses by imputing them according to the following two extreme case scenarios (Hollis 1999):
‐ Extreme case analysis favouring the experimental intervention ('best‐worst' case scenario): none of the dropouts/participants lost from the experimental arm, but all of the dropouts/participants lost from the control arm experienced the outcome, including all randomised participants in the denominator.
‐ Extreme case analysis favouring the control ('worst‐best' case scenario): all dropouts/participants lost from the experimental arm, but none from the control arm experienced the outcome, including all randomised participants in the denominator.
Evaluación de la heterogeneidad
We checked for heterogeneity through visual inspection of the forest plots by using a standard Chi2 test and a significance level of α = 0.1. In view of the low power of such tests, we also examined heterogeneity by using the I2 statistic (Higgins 2002); I2 values of 50% or more indicate a substantial level of heterogeneity (Higgins 2003). When heterogeneity was found, we attempted to determine potential reasons for it by examining individual trial characteristics and subgroups. For heterogeneity adjustment of the required information size, we used diversity, the D2 statistic (Wetterslev 2009).
Evaluación de los sesgos de notificación
Whenever we had 10 or more trials, we drew funnel plots to assess reporting biases from the individual trials by plotting the risk ratio (RR) on a logarithmic scale against its standard error (Egger 1997; Higgins 2011).
For dichotomous outcomes, we tested asymmetry using the Harbord test in case tau2 was less than 0.1 (Harbord 2006), and we used Rücker 2008 in case tau2 was more than 0.1. We planned to use the regression asymmetry test (Egger 1997) and the adjusted rank correlation coefficient (Begg 1994) for our continuous outcome, health‐related quality of life.
Síntesis de los datos
Meta‐analysis
For the statistical analyses, we used Review Manager 5 (RevMan 2014). For dichotomous outcomes, we calculated the Mantel‐Haenszel risk ratios (RRs). We planned to use the mean difference (MD) for the continuous outcome, health‐related quality of life.
We performed the analyses using the intention‐to‐treat (ITT) principle, including all randomly assigned participants, irrespective of completeness of data.
Review Manager 5 does not include trials with zero events in both intervention groups when calculating RR (RevMan 2014). To account for trials with zero events, we used Trial Sequential Analysis with a continuity correction (Thorlund 2011; TSA 2011).
We compared the intervention effects in subgroups of trials using RevMan 2014.
We intended to calculate the number‐needed‐to‐treat for an additional beneficial outcome (NNTB).
Trial Sequential Analysis
As a sensitivity analysis for our GRADE assessment of imprecision (see below), we used Trial Sequential Analysis which considers choice of statistical model (fixed or random) and diversity (Thorlund 2011; TSA 2011). We calculated the diversity‐adjusted required information size (DARIS, i.e. the number of participants needed in a meta‐analysis to detect or reject a certain intervention effect) (Brok 2008; Wetterslev 2008; Brok 2009; Wetterslev 2009; Thorlund 2010; Wetterslev 2017).
The underlying assumption of Trial Sequential Analysis is that testing for statistical significance may be performed each time a new trial is added to the meta‐analysis. We added the trials according to the year of publication, and, if more than one trial was published in a year, we added the trials alphabetically according to the last name of the first author. On the basis of the DARIS, we constructed the trial sequential monitoring boundaries for benefit, harm, and futility (Wetterslev 2008; Wetterslev 2009; Thorlund 2011; Wetterslev 2017). These boundaries determine the statistical inference one may draw regarding the cumulative meta‐analysis that has not reached the DARIS; if the trial sequential monitoring boundary for benefit or harm is crossed before the DARIS is reached, firm evidence may be established and further trials may be superfluous. However, if the boundaries for benefit or harm are not crossed, it is most probably necessary to continue doing trials in order to detect or reject a certain intervention effect. However, if the cumulative Z‐curve crosses the trial sequential monitoring boundaries for futility, no more trials may be needed.
In our Trial Sequential Analysis of the two primary dichotomous outcomes, we based the DARIS on the event proportion in the control group; assuming a plausible relative risk reduction for mortality of 10% and a relative risk reduction for serious adverse events of 5%; a risk of type I error of 2.5% due to the three primary outcomes (Jakobsen 2014); a risk of type II error of 20%; and the diversity of the included trials in the meta‐analysis. For the continuous outcome, health‐related quality of life, we planned to estimate the DARIS using a minimal relevant difference of 10% of the mean response observed in the control group; the standard deviation of the meta‐analysis; alpha of 2.5% due to the three primary outcomes (Jakobsen 2014); beta of 20%; and the diversity as estimated from the trials in the meta‐analysis (Wetterslev 2009). We also calculated the Trial Sequential Analysis‐adjusted confidence intervals (CI) (Thorlund 2011; Wetterslev 2017).
In our Trial Sequential Analysis of secondary outcomes, we based the DARIS for dichotomous outcomes on the event proportion in the control group; we made an assumption of a relative risk reduction of 10% for refractory ascites, renal impairment, other liver‐related complications, and non‐severe adverse events; a type I error risk of 2.0% due to the four secondary outcomes (Jakobsen 2014); a risk of type II error of 20%; and the diversity of the included trials in the meta‐analysis.
A more detailed description of Trial Sequential Analysis and software program can be found at www.ctu.dk/tsa/ (Thorlund 2011).
Assessment of significance based on the standard meta‐analysis method and Trials Sequential Analysis method
We conducted both fixed‐effect and random‐effects model meta‐analyses. If the fixed‐effect and random‐effects models showed different results, then the most conservative result (the analysis with the highest P value, i.e. closest to the null hypothesis) was chosen as the main result of the two analyses (Jakobsen 2014).
We considered a P value of 0.025 or less, two‐tailed, as statistically significant if the DARIS was reached due to our three primary outcomes (Jakobsen 2014). We considered a P value of 0.02 or less, two‐tailed, as statistically significant if the required information size was reached due to our four secondary outcomes. We used the eight‐step procedure to assess if the thresholds for significance were crossed (Jakobsen 2014). We presented heterogeneity using the I2 statistic (Higgins 2002). We presented the results of the individual trials and meta‐analyses in the form of forest plots.
Where data were only available from one trial, we used Fisher's exact test for dichotomous data (Fisher 1922). We planned to use Student's t‐test for continuous data such as 'health‐related quality of life' (Student 1908).
Análisis de subgrupos e investigación de la heterogeneidad
We planned to perform the following subgroup analyses:
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risk of bias, analysing separately randomised clinical trials at low risk of bias and trials at high risk of bias;
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type of plasma expanders, analysing separately randomised clinical trials according to the plasma expander used;
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refractory ascites, analysing separately randomised clinical trials including participants with refractory ascites and trials including participants without refractory ascites;
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modality of paracentesis, analysing separately randomised clinical trials in which partial paracentesis repeated until disappearance of ascites were used, and randomised clinical trials in which total, one‐session paracentesis were used;
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length of follow‐up, analysing separately randomised clinical trials with up to one month follow‐up (short follow‐up trials) and trials with a follow‐up longer than one month (long follow‐up trials);
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trials without for‐profit support compared to trials with or unknown for‐profit support (see Appendix 2 for definition) (Lundh 2017).
To determine whether a statistically significant subgroup difference was detected, we considered the P value from the test for subgroup differences. We used the test to assess the difference between the pooled effect estimates for each subgroup. A P value of less than 0.1 showed a significant subgroup effect.
Análisis de sensibilidad
For sensitivity analyses, see Dealing with missing data and 'Summary of findings' tables paragraphs.
'Summary of findings' tables
We assessed the certainty of the evidence using the GRADE system to present review results in 'Summary of findings' (SoF) tables, using GRADEPro 3.6 (http://ims.cochrane.org/revman/gradepro). In SoF tables, we included three Primary outcomes as well as four Secondary outcomes. We designed two Sof tables as we have two comparisons (Summary of findings table 1; Summary of findings table 2). A SoF table consists of three parts: information about the review, a summary of the statistical results, and the grade of the certainty of evidence. The assessment of certainty of the available evidence is comprised of the number of studies, the types of studies (randomised or observational), and five factors including within study risk of bias, inconsistency of results (heterogeneity), indirectness of evidence (population, intervention, control, outcomes), imprecision of results, and publication bias that affect the certainty of the evidence (Guyatt 2008; Balshem 2011; Guyatt 2011a; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt 2011g; Guyatt 2011h; Guyatt 2013a; Guyatt 2013b; Guyatt 2013c; Mustafa 2013). The five factors are used to judge whether the certainty of the collected evidence should be downgraded or upgraded.
As sensitivity analysis, we compared imprecision evaluation with GRADE based on the GRADE Handbook, with GRADE based on authors' choice of plausible relative risk reduction (RRR) and multiplicity correction, and according to our Trial Sequential Analysis (TSA) with a similar choice of plausible RRR and multiplicity correction, in addition to considering the choice of meta‐analytic model and diversity (Jakobsen 2014; Castellini 2018; Gartlehner 2018).
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies.
Results of the search
The reference flow is summarised in the study flow diagram (Figure 1). For detailed search strategies, see Appendix 1.
Study flow diagram.
We identified 1079 references through electronic searches of the Cochrane Hepato‐Biliary Group Controlled Trials Register (n = 86), Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (n = 146), MEDLINE (n = 98), Embase (n = 234), LILACS (n = 21), Science Citation Index EXPANDED and Conference Proceedings Citation Index – Science (Web of Science) (n = 212), and three Chinese database including CNKI (China National Knowledge Infrastructure) (n = 154), VIP (n = 88), and Wanfang (n = 40). We also searched databases of ongoing trials (www.clinicaltrials.gov/ and www.controlled‐trials.com/) (with links to several databases). One not yet recruiting trial was retrieved (NCT03202524). In addition, we searched European Medicines Agency (EMA), US Food and Drug Adminitration (FDA), and the World Health Organization International Clinical Trials Registry Platform (ICTRP 2011) until January 2019. One ongoing trial without interim data was retrieved (EudraCT 2010‐019783‐37). We did not apply any language or document type restrictions.
After the removal of 338 duplicates, we obtained 743 references. We then excluded 705 clearly irrelevant references through screening titles and reading abstracts. We retrieved 38 full‐text articles for further assessment. No references were identified through scanning reference lists of the identified randomised trials. Thirty‐four references were reports of 27 trials which fulfilled the inclusion criteria of our review.
Two trials were used only in a qualitative synthesis (García‐Compeán 2002; Degoricija 2003). García‐Compeán 2002 did not report the number of randomised participants for each group. Furthermore, they re‐randomised participants if readmitted for paracentesis during the follow‐up. Degoricija 2003 did not report the number of events per intervention group.
Included studies
Trial characteristics
We included 27 randomised clinical trials. Twenty‐four trials were published as full‐text articles and three trials as abstracts.
Two trial publications were in Korean (Kang 1998; Baik 2000) and two trials in Spanish (Bertrán 1991; Hernández Pérez 1995) languages. The remaining 23 trials were published in English.
The trials were conducted in Canada, China, Croatia, France, Germany, India, Italy, Korea, Pakistan, Russia, Spain, and the United States. All trials were performed in specialised units in intensive care or semi‐intensive care settings.
All trials had a parallel group design except one which used a cross‐over trial design (Sola‐Vera 2003). From the 26 trials with a parallel group design, one trial had three intervention groups (Ginès 1996), one had six intervention groups (Descos 1983), and two trials had five intervention groups (Degoricija 2003; Al Sebaey 2012). The remaining 22 trials had two intervention groups.
Ten trials seemed not to have been funded by industry (Descos 1983; Ginès 1988; Planas 1990; Simonetti 1991; Fassio 1992; Luca 1995; Sola‐Vera 2003; Moreau 2006; Al Sebaey 2012; Khan 2015). Twelve trials were considered unclear about funding (Bertrán 1991; Bruno 1992; Méndez 1991; García‐Compeán 1993; Hernández Pérez 1995; Kang 1998; Mehta 1998; Baik 2000; Zhao 2000; García‐Compeán 2002; Degoricija 2003; Abdel‐Khalek 2010). Five trials were considered funded by industry or a for‐profit institution (Smart 1990; Salerno 1991; Ginès 1996; Graziotto 1997; Altman 1998).
Participant characteristics
The trials included 1592 randomised participants with a mean sample size of 59 participants (range 12 to 289 participants). The mean age of the participants was 56.4 years with a mean range of 42.0 to 61.3 years. The mean proportion of males in the trial groups was 67.7%. The reported aetiology of cirrhosis was alcoholic in 60.9% of the participants (range 13% to 94%; 20 trials) and viral in 27.8% of the participants (range 2% to 70.6%; 17 trials). According to the Child‐Pugh classification, most participants had an intermediate to advanced stage of cirrhosis. Nine trials reported a mean Child‐Pugh score of 10.4 points (range 9.6 to 12), and seven trials reported that between 33% and 60% of the participants were in class B Child‐Pugh, and between 37% to 58% of the participants were in class C Child‐Pugh. One trial reported that 65% of the participants were in class C and for the remaining 35%, the class was not reported. In three trials, the proportion of participants in class A Child‐Pugh ranged between 2.9% and 8.3% (Bertrán 1991; Bruno 1992; Sola‐Vera 2003). In the remaining eleven trials, this information was not provided. Almost all trials excluded participants with hepatocellular carcinoma as well as recent gastrointestinal bleeding, infections, or hepatic encephalopathy. In Salerno 1991, 30% of participants had hepatocellular carcinoma. Seven trials assessed the effects of treatments in people with refractory ascites according to authors' diagnostic definitions (Smart 1990; Méndez 1991; Salerno 1991; Simonetti 1991; Graziotto 1997; Mehta 1998; Abdel‐Khalek 2010) (Characteristics of included studies). The remaining 20 trials included participants without refractory ascites because the mean value of blood urea was 21.86 + SD 8.58 mg/dL and the mean value of serum creatinine was 0.96 + SD 0.12 mg/dL (Characteristics of included studies). The proportion of people with renal impairment was reported in 10 trials (Ginès 1988; Planas 1990; Fassio 1992; Hernández Pérez 1995; Ginès 1996; Altman 1998; Zhao 2000; García‐Compeán 2002; Sola‐Vera 2003; Moreau 2006); it ranged from 0% in Altman 1998 and Fassio 1992 to 28% in García‐Compeán 2002, with a mean of 12%. Seventeen trials reported mean arterial pressure of 88 (SD 5.6) mmHg, and 15 trials reported the mean renin activity of 10.42 (SD 5.73) ng/mL/hour.
Paracentesis characteristics
All trial participants were treated with paracentesis. Total paracentesis completed in a single session was used in the experimental and control groups of 20 trials (Descos 1983; Planas 1990; Bertrán 1991; Méndez 1991; Salerno 1991; Bruno 1992; García‐Compeán 1993; Hernández Pérez 1995; Luca 1995; Ginès 1996; Graziotto 1997; Kang 1998; Mehta 1998; Baik 2000; García‐Compeán 2002; Sola‐Vera 2003; Moreau 2006; Abdel‐Khalek 2010; Al Sebaey 2012; Khan 2015). Partial paracentesis, repeated until disappearance of ascites, was used in both intervention groups of four trials (Ginès 1988; Fassio 1992; Altman 1998; Zhao 2000). Single‐session paracentesis was used in the experimental group and partial paracentesis in the control group of two trials (Smart 1990; Simonetti 1991); the paracentesis was repeated until disappearance of ascites on alternate days in Simonetti 1991 and every day in Smart 1990. A single paracentesis of 6 L was performed in Degoricija 2003.
Intervention characteristics
Out of the 27 trials, five trials, including 271 participants, assessed plasma volume expansion versus no plasma volume expansion (Descos 1983; Ginès 1988; García‐Compeán 1993; Luca 1995; Baik 2000). Four of these trials used albumin as a plasma expander (Ginès 1988; García‐Compeán 1993; Luca 1995; Baik 2000) and the remaining trial with six trial groups assessed plasma volume expansion with intravenous infusion of filtrated ascitic fluid versus intravenous infusion of unmodified ascitic fluid versus no plasma expansion, or versus several different diuretic treatments (Descos 1983). For the purpose of our review, we put together, in the experimental group, the data from people treated with intravenous infusion of filtrated or unmodified ascitic fluid.
Twenty‐two trials, including 1321 participants, assessed the effect of a plasma volume expander versus another plasma volume expander. Overall, the experimental treatments were Dextran 70 in five trials (Planas 1990; Bertrán 1991; Fassio 1992; Hernández Pérez 1995; Ginès 1996) and Dextran 40 in one trial (García‐Compeán 2002); polygeline in five trials (Salerno 1991; Ginès 1996; Degoricija 2003; Moreau 2006; Khan 2015); hydroxyethyl starch in five trials (Méndez 1991; Altman 1998; Kang 1998; Abdel‐Khalek 2010; Al Sebaey 2012); fresh frozen plasma in one trial (Degoricija 2003); intravenous infusion of ascitic fluid in four trials (Smart 1990; Simonetti 1991; Bruno 1992; Graziotto 1997); saline solution in one trial (Sola‐Vera 2003); and mannitol(um) in one trial (Zhao 2000). In 21 trials, albumin was used as the control intervention. Dextran 70 and polygeline were assessed in a three‐armed trial compared with albumin (Ginès 1996). Albumin, fresh frozen plasma and polygeline plus bed rest, no plasma expanders without bed rest and diuretic treatment without paracentesis and bed rest were compared in a 5‐armed trial. For the purpose of this review, we used the data from the first three intervention groups (Degoricija 2003). Hydroxyethyl starch, terlipressin, midodrine, and albumin in two different doses (6 g/L of ascitic fluid in one group and 3 g/L in another group) were compared in a five‐armed trial (Al Sebaey 2012). For the purpose of this review, we compared the hydroxyethyl starch group with the two albumin groups, put together (Al Sebaey 2012). We did not use the data from the other two intervention groups of this trial. Intravenous infusion of ascitic fluid was compared with polygeline in one trial (Mehta 1998).
Overall, 175 participants were treated with Dextran 70, 209 with polygeline, 135 with hydroxyethyl starch, 77 with intravenous ascitic fluid infusion, 35 with 3.5% saline, and 32 with mannitol, and 10 participants with fresh frozen plasma versus 579 participants treated with albumin. The number of participants treated by Dextran 40 is unknown (see above, García‐Compeán 2002).
The dose of the plasma expanders for each litre of removed ascitic fluid was as follows: for albumin 2 g to 10 g, for dextran 6 g to 8 g, for hydroxyethyl starch 7.7 g to 13 g, for polygeline 4 g to 8 g, for 3.5% saline 170 mL, for mannitol 8 g to 16 g, and for fresh frozen plasma 100 mL.
The mean volume (± SD) of removed ascitic fluid reported in 24 trials was 8.1 L (SD 2.96) (range 4.0 L to 15.9 L). Diuretic treatment was used after paracentesis in 13 trials.
If recurrence of ascites occurred during the follow‐up period, the participants in seven trials were treated with the same schedule to which they were randomised originally (Ginès 1988; Planas 1990; Salerno 1991; Simonetti 1991; Fassio 1992; Ginès 1996; Abdel‐Khalek 2010). Participants were treated with an alternative treatment in one trial (Sola‐Vera 2003). As this trial was a cross‐over trial, we used the results from the first period of the trial on day 6 after paracentesis for all outcomes, except for the recurrence of ascites for which data were reported after discharge of trial participants.
Follow‐up and withdrawals
Fifteen trials reported analyses of outcomes within one month: at 24 hours in Luca 1995, at two days in Baik 2000, at three days in Kang 1998, at five days in Méndez 1991 and García‐Compeán 1993, at six days in Degoricija 2003, Sola‐Vera 2003, Al Sebaey 2012 and Khan 2015, at eight days in Bruno 1992, at 14 days in Hernández Pérez 1995, at 15 days in Altman 1998, and at one month in Descos 1983 and Bertrán 1991. In Mehta 1998, the median follow‐up was 17.5 days.
The other 12 trials had a follow‐up longer than a month (Ginès 1988; Planas 1990; Smart 1990; Salerno 1991; Simonetti 1991; Fassio 1992; García‐Compeán 2002; Ginès 1996; Graziotto 1997; Zhao 2000; Moreau 2006; Abdel‐Khalek 2010). In Sola‐Vera 2003 (a cross‐over trial), the follow‐up was longer than one month only for recurrence of ascites, whereas the other outcomes were recorded on day six.
Fifteen trials followed up the participants after their discharge from hospital (Descos 1983; Ginès 1988; Planas 1990; Smart 1990; Salerno 1991; Simonetti 1991; Fassio 1992; Ginès 1996; Graziotto 1997; Altman 1998; Mehta 1998; García‐Compeán 2002; Sola‐Vera 2003; Moreau 2006; Abdel‐Khalek 2010).
In Ginès 1996 and Sola‐Vera 2003 trials, participants were followed up after discharge, but the authors reported data on the outcomes of interest only for the first hospitalisation (Ginès 1996), and on the sixth day after paracentesis (Sola‐Vera 2003). Therefore, we included them in the analysis of trials with a short follow‐up.
The mean follow‐up period was 136 days (range 1 to 638) in 25 trials (Descos 1983; Ginès 1988; Planas 1990; Bertrán 1991; Méndez 1991; Salerno 1991; Simonetti 1991; Bruno 1992; Fassio 1992; García‐Compeán 1993; Hernández Pérez 1995; Luca 1995; Ginès 1996; Graziotto 1997; Altman 1998; Kang 1998; Baik 2000; Zhao 2000; García‐Compeán 2002; Degoricija 2003, Sola‐Vera 2003; Moreau 2006; Abdel‐Khalek 2010; Al Sebaey 2012; Khan 2015). The median follow‐up period was 231 days in Smart 1990 and 17.5 days in Mehta 1998.
In the five trials comparing plasma expansion versus no plasma expansion, the percentage of dropouts and withdrawals was 1.21%. In the twenty‐one trials comparing plasma expanders versus albumin, the percentage of reported dropouts and withdrawals was 5.27%.
Excluded studies
Characteristics of excluded studies table presents the excluded studies with the reason for their exclusion.
Three studies were excluded. Two studies were comparative, and not randomised trials (Zaak 2001; Nasr 2010). One study, published as abstract for the first time in 1990 (Antillon 1990), was still ongoing in 1991 (Antillon 1991). We could obtain no further information on the study.
Risk of bias in included studies
We based our assessment on published information and on that received from trial authors (Figure 2; Figure 3).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Allocation
Allocation sequence generation
Sixteen trials were at low risk of bias regarding allocation sequence generation (Ginès 1988; Planas 1990; Salerno 1991; Simonetti 1991; Bruno 1992; Fassio 1992; García‐Compeán 1993; Luca 1995; Ginès 1996; Altman 1998; García‐Compeán 2002; Sola‐Vera 2003; Degoricija 2003, Moreau 2006; Abdel‐Khalek 2010; Khan 2015). The remaining 11 trials were at unclear risk of bias.
Allocation concealment
Five trials were at low risk of bias regarding allocation concealment (Smart 1990; Salerno 1991; Simonetti 1991; Altman 1998; Sola‐Vera 2003). The risk of bias in the remaining 22 trials was unclear.
Blinding
Blinding of participants and personnel
All the 27 trials were at unclear risk of bias regarding blinding of participants and personnel.
Blinding of outcome assessment
We judged only one trial at low risk of bias regarding blinding of outcome assessment (Sola‐Vera 2003). The remaining 26 trials were at unclear risk of bias.
Incomplete outcome data
We judged twenty trials to be at low risk of bias regarding attrition bias. The remaining seven trials were at unclear risk of bias (Bertrán 1991; Méndez 1991; Ginès 1996; Kang 1998; Baik 2000; Degoricija 2003; Al Sebaey 2012).
Selective reporting
Twelve trials aimed to assess haemodynamic or neurohumoral changes after a short follow‐up period after paracentesis (Bertrán 1991; Méndez 1991; Bruno 1992; García‐Compeán 1993; Hernández Pérez 1995; Luca 1995; Altman 1998; Kang 1998; Baik 2000; Degoricija 2003; Al Sebaey 2012; Khan 2015).
Only four trials reported serious adverse events (Descos 1983; Luca 1995; Moreau 2006; Khan 2015). No trials reported data on refractory ascites. We followed the recommendation of the Cochrane Handbook, which stated that "review authors should look hard for the evidence of collection by study investigators of a small number of key outcomes that are routinely measured in the area in question”. In addition, most trials were published before a formal definition of serious adverse events and refractory ascites. So, the lack of the reporting of these two outcomes did not necessarily put the trials at high risk of bias.
Overall, we judged ten trials to be at high risk of bias of selective outcome reporting because information on mortality or more than one secondary outcome was missing (Bertrán 1991; Méndez 1991; Hernández Pérez 1995; Ginès 1996; Altman 1998; Mehta 1998; Baik 2000; García‐Compeán 2002; Degoricija 2003; Al Sebaey 2012). One trial was at unclear risk of bias (Khan 2015). The remaining sixteen trials were judged to be at low risk of bias (Descos 1983; Ginès 1988; Planas 1990; Smart 1990; Salerno 1991; Simonetti 1991; Bruno 1992; Fassio 1992; García‐Compeán 1993; Luca 1995; Graziotto 1997; Kang 1998; Zhao 2000; Sola‐Vera 2003; Moreau 2006; Abdel‐Khalek 2010).
Other potential sources of bias
We could suspect no other potential sources of bias in nineteen trials (Descos 1983; Ginès 1988; Planas 1990; Smart 1990; Bertrán 1991; Salerno 1991; Simonetti 1991; Bruno 1992; Fassio 1992; García‐Compeán 1993; Hernández Pérez 1995; Luca 1995; Ginès 1996; Graziotto 1997; Altman 1998; Mehta 1998; Zhao 2000; Sola‐Vera 2003; Abdel‐Khalek 2010). We judged the remaining eight trials as having unclear risk because they were published as abstracts (Méndez 1991; Al Sebaey 2012), or the information was not enough (Kang 1998; Baik 2000; Moreau 2006; Khan 2015), or because of the characteristics of the design and analysis (García‐Compeán 2002; Degoricija 2003).
Overall risk of bias
We judged all trials to be at high risk of bias because they were assessed as having an uncertain risk of bias or a high risk of bias in one or more of the bias risk domains.
Effects of interventions
See: Summary of findings for the main comparison Plasma expanders versus no plasma expanders for people with cirrhosis and large ascites treated with abdominal paracentesis; Summary of findings 2 Other plasma expanders versus albumin for people with cirrhosis and large ascites treated with abdominal paracentesis
Plasma expanders versus no plasma expander
Primary outcomes
All‐cause mortality
Four trials provided data on mortality with a mean follow‐up of 64 days. Three trials had a follow‐up less than one month. No mortality occurred in two of the trials (García‐Compeán 1993; Luca 1995). The effect of plasma expanders (albumin and ascites infusion) compared with no plasma expander in terms of reduction in all‐cause mortality was very uncertain (RR 0.52, 95% CI 0.06 to 4.83; 248 participants; 4 trials; I2 = 76%; Analysis 1.1; Descos 1983; Ginès 1988; García‐Compeán 1993; Luca 1995).
We assessed the certainty of the evidence with GRADE as very low. We downgraded the evidence by four levels because all trials were at high risk of bias; there was high heterogeneity; and the required information size was not reached (summary of findings Table for the main comparison; Table 1).
| Comparison of imprecision evaluation with GRADE based on the GRADE Handbook, with GRADE based on authors' choice of plausible relative risk reduction and multiplicity correction, and according to our Trial Sequential Analysis with a similar choice of plausible relative risk reduction and multiplicity correction, in addition to considering the choice of meta‐analytic model and diversity | |||||||
| Outcome | Proportion in control group | Relative risk reduction | Alpha | Beta | Diversity | Required information size (OIS or DARIS) | Downgrading of evidence for imprecision based on required information size |
| All‐cause mortality ‐‐ GRADE Handbook | 18% | 25% | 5% | 20% | Not used | 2056 | One level |
| All‐cause mortality ‐‐ GRADE plausible RRR | 18% | 10% | 2.5% | 20% | Not used | 16,634 | One level |
| All‐cause mortality ‐‐ TSA | 18% | 10% | 2.5% | 20% | 88% | 143,664 | One level |
| Serious adverse events ‐‐ GRADE Handbook (1) | |||||||
| Serious adverse events ‐‐ GRADE plausible RRR (1) | |||||||
| Serious adverse events ‐‐ TSA (1) | |||||||
| Health‐related quality of life ‐‐ GRADE Handbook | No data | ||||||
| Health‐related quality of life ‐‐ GRADE plausible RRR | No data | ||||||
| Health‐related quality of life ‐‐ TSA | No data | ||||||
| Refractory ascites ‐‐ GRADE Handbook | No data | ||||||
| Refractory ascites ‐‐ GRADE plausible RRR | No data | ||||||
| Refractory ascites ‐‐ TSA | No data | ||||||
| Renal impairment ‐‐ GRADE Handbook | 9.8% | 25% | 5% | 20% | Not used | 4100 | One level |
| Renal impairment ‐‐ GRADE plausible RRR | 9.8% | 10% | 2.00% | 20% | Not used | 35,290 | One level |
| Renal impairment ‐‐ TSA | 9.8% | 10% | 2.00% | 20% | 0% | 35,293 | One level |
| Other liver‐related complications ‐‐ GRADE Handbook | 9% | 25% | 5% | 20% | Not used | 4498 | One level |
| Other liver‐related complications ‐‐ GRADE plausible RRR | 9% | 10% | 2.00% | 20% | Not used | 38,750 | One level |
| Other liver‐related complications ‐‐ TSA | 9% | 10% | 2.00% | 20% | 0% | 38,752 | One level |
| Non‐serious adverse events ‐‐ GRADE Handbook | 6.25% | 25% | 5% | 20% | Not used | 6670 | One level |
| Non‐serious adverse events ‐‐ GRADE plausible RRR | 6.25% | 10% | 2.00% | 20% | Not used | 56,464 | One level |
| Non‐serious adverse events ‐‐ TSA | 6.25% | 10% | 2.00% | 20% | 0% | 56,467 | One level |
(1) Serious adverse events: 0/68 in plasma expander group and 0/40 in no plasma expander group, RR 1.00 (95% CI 0.00 to 217…)
OIS: optimal information size; DARIS: diversity‐adjusted required information size; RRR: relative risk reduction; TSA: Trial Sequential Analysis
Including the two trials with zero deaths in the Trial Sequential Analysis produced a comparable result (RR 0.64; 95% CI 0.14 to 2.93; P = 0.56; D2= 88%).
The Trial Sequential Analysis of this comparison was based on a mortality of 18% in the control group, a relative risk reduction of 10% with albumin or other plasma expanders, a type I error of 2.5%, a type II error of 20% (80% power), and 88% diversity. The DARIS was 143,664 participants. Due to the fact that only 248 participants were recruited (which is 0.17% of the DARIS of 143,664 participants), the Trial Sequential Analysis program could not construct an interpretable figure and could not calculate Trial Sequential Analysis‐adjusted CIs.
Subgroup analysis
We could not perform subgroup analysis of trials according to their risk of bias because all the trials were assessed at high risk of bias; and according to participants with and participants without refractory ascites because all the trials included participants without refractory ascites.
Type of plasma expanders
The test for subgroup differences comparing the effects of each type of plasma expander (albumin and ascites infusion) suggested a difference between the plasma expanders used (P = 0.04, I² = 75.3%; Analysis 1.1). In trials comparing albumin versus no plasma expander, RR was 1.27, 95% CI 0.75 to 2.17; 158 participants; 3 trials; I2 not calculated because 2/3 of the trials had 0 events, Analysis 1.1.1; Ginès 1988; García‐Compeán 1993; Luca 1995) whereas in trials comparing intravenous ascitic fluid infusion versus no plasma expander RR was 0.13, 95% CI 0.02 to 1.13; 90 participants; 1 trial (Analysis 1.1.2; Descos 1983).
Modality of paracentesis
The test for subgroup differences comparing the effects of plasma expander versus no plasma expander in people treated by partial or total paracentesis suggested a difference between the two subgroups (P = 0.04, I² = 75.3%; Analysis 2.1). In trials in which partial paracentesis were used, RR was 1.27, 95% CI 0.75 to 2.17; 105 participants; 1 trial (Analysis 2.1.1; Ginès 1988) whereas the subgroup of trials in which total paracentesis were used, RR was 0.13, 95% CI 0.02 to 1.13; 143 participants; 3 trials; I2 not calculated because 2/3 of the trials had 0 events (Analysis 2.1.2; Descos 1983; García‐Compeán 1993; Luca 1995).
Length of follow‐up
The test for subgroup differences comparing the effects of plasma expander versus no plasma expander in trials with a short follow‐up (up to one month) to trials with a long follow‐up (more than one month) suggested a difference (P = 0.04, I² = 75.3%; Analysis 3.1). In trials with a short follow‐up, RR was 0.13, 95% CI 0.02 to 1.13; 143 participants; 3 trials; I2 not calculated because 2/3 of the trials had 0 events (Analysis 3.1.1; Descos 1983; García‐Compeán 1993; Luca 1995) whereas in the trial with a long follow‐up RR was 1.27, 95% CI 0.75 to 2.17; 105 participants; 1 trial; I2 not applicable (Analysis 3.1.2; Ginès 1988).
For‐profit support
In the subgroup of trials without for‐profit funding, RR was 0.52, 95% CI 0.06 to 4.83; 213 participants; 3 trials; I2 = 76% (Analysis 4.1.1). In the only trial without information on for‐profit funding, no deaths were reported (García‐Compeán 1993).
Sensitivity analysis
The best‐worst (RR 0.49, 95% CI 0.06 to 3.76; 248 participants; 4 trials; I2 = 73%; Analysis 5.1) and the worst‐best scenario analyses (RR 0.87, 95% CI 0.28 to 2.76; 248 participants; 4 trials; I2 = 60%; Analysis 6.1) both suggested neutral results.
Serious adverse events
Out of the five trials assessing plasma volume expansion versus no plasma volume expansion, two trials reported that there were no serious adverse events (Descos 1983; Luca 1995). The remaining three trials did not mention if serious adverse events occurred (Ginès 1988; García‐Compeán 1993; Baik 2000) (Analysis 1.2).
We assessed the certainty of the evidence with GRADE as very low. We downgraded the evidence by four levels because all trials were at high risk of bias; there was substantial imprecision due to the lack of events (summary of findings Table for the main comparison). The required information size was not reached (Table 1).
Subgroup analysis
We could not perform subgroup analysis of trials according to their risk of bias because the two trials were assessed at high risk of bias; according to participants with and participants without refractory ascites because the two trials included participants without refractory ascites; according to modality of paracentesis because the two trials performed total paracentesis; according to length of follow‐up because the two trials had short follow‐up; and according to for‐profit funding because the two trials were without for‐profit funding (Subgroup analysis and investigation of heterogeneity).
Health‐related quality of life
None of the included trials reported health‐related quality of life.
Secondary outcomes
Refractory ascites
None of the included trials provided information on refractory ascites.
Renal impairment
Four trials reported data on renal impairment (Ginès 1988; García‐Compeán 1993; Luca 1995; Baik 2000). All four trials used albumin as a plasma expander. In two of the trials, renal impairment did not occur (Luca 1995; Baik 2000). The effect of albumin versus no plasma expander on renal impairment was uncertain (RR 0.32, 95% CI 0.02 to 5.88; 181 participants; 4 trials; I2 = 67%; Analysis 1.3).
We assessed the certainty of the evidence with GRADE as very low. We downgraded the evidence by five levels because all trials were at high risk of bias; there was high heterogeneity; there were few events and the CI included appreciable benefit and harm (summary of findings Table for the main comparison). The required information size was not reached (Table 1).
Including the two trials with zero events in Trial Sequetial Analysis produced a comparable result (RR 1.02, 95% CI 0.16 to 6.43; P = 0.98).
The Trial Sequential Analysis of the four trials assessing plasma expander versus no plasma expander was constructed based on the renal impairment proportion of 9.8% in the control group, a relative risk reduction of 10.0% with plasma expander, a type I error of 2.00%, and a type II error of 20% (80% power). There was no diversity (D2 = 0%). The DARIS was 35,293 participants. Due to the fact that only 181 participants were recruited (0.51% of the DARIS of 35,293 participants), the Trial Sequential Analysis program could not construct an interpretable figure and could not calculate Trial Sequential Analysis‐adjusted CIs.
Subgroup analysis
None of the first three planned subgroup analyses could be performed because the risk of bias in the four trials providing data on renal impairment was high, all the four trials included participants without refractory ascites, and all the four trials used albumin.
Modality of paracentesis
The test for subgroup differences comparing the effects of plasma expander versus no plasma expander on renal impairment in participants treated by partial paracentesis and by total paracentesis showed no difference (P = 0.11, I² = 60.5%; Analysis 2.2). There was no evidence of a difference in renal impairment after partial paracentesis (RR 0.07, 95% CI 0.00 to 1.16; 105 participants; 1 trial; Analysis 2.2.1; Ginès 1988) and after total paracentesis (RR 1.06, 95% CI 0.17 to 6.70; 76 participants; 3 trials; I2 not applicable because 2/3 of the trials had 0 events; Analysis 2.2.2; García‐Compeán 1993; Luca 1995; Baik 2000).
Length of follow‐up
The test for subgroup differences comparing the effects of plasma expander versus no plasma expander in trials with a short follow‐up (up to one month) compared to trials with a long follow‐up (more than one month) showed no difference (P = 0.11, I² = 60.5; Analysis 3.2). We found no evidence of a difference in the effect of albumin‐treated participants and the untreated participants in trials with up to one month follow‐up in renal impairment (RR 1.06, 95% CI 0.17 to 6.70; 53 participants; 2 trials; I2 not applicable because 1/2 of the trials had 0 events; Analysis 3.2.1; García‐Compeán 1993; Luca 1995), and the same was observed between the albumin‐treated participants and the untreated participants in trials with a follow‐up of more than one month (RR 0.07, 95% CI 0.00 to 1.16; 105 participants; 1 trial; Analysis 3.2.2).
For‐profit support
The test for subgroup differences comparing for‐profit support showed no differences between the two subgroups (P = 0.11, I2 = 60.5%; Analysis 4.2). We found no difference in renal impairment either in the subgroup of trials without for‐profit funding (RR 0.07, 95% CI 0.00 to 1.16; 123 participants; 2 trials; I2 not applicable because 1/2 trial had 0 events; Analysis 4.2.1) or in the subgroup of trials without information on for‐profit funding (RR 1.06, 95% CI 0.17 to 6.70; 58 participants; 2 trials; I2 not applicable because 1/2 trial had 0 events; Analysis 4.2.2).
Other liver‐related complications
Four trials reported data on other liver‐related complications such as gastrointestinal bleeding, hepatic encephalopathy, or infections (Descos 1983; Ginès 1988; García‐Compeán 1993; Luca 1995). The meta‐analysed results of these four trials showed no evidence of a difference in the effect of plasma expander (albumin and infusion of ascitic fluid) versus no plasma expander on other liver‐related complications (RR 1.61, 95% CI 0.79 to 3.27; 248 participants; 4 trials; I2 = 0%; Analysis 1.4).
Including the trial with zero events in Trial Sequential Analysis produced a comparable result (RR 1.61, 95% CI 0.79 to 3.27; P = 0.19).
We assessed the certainty of the evidence with GRADE as very low. We downgraded the evidence by three levels because all trials were at high risk of bias; and there was imprecision: the required information size was not reached (summary of findings Table for the main comparison; Table 1).
Trial Sequential Analysis was constructed based on risk of other liver‐related complications of 9% in the control group, a relative risk reduction of 10% with plasma expander, a type I error of 2.00%, and a type II error of 20% (80% power). There was low diversity (D2 = 0%). The DARIS was 38,752 participants. Due to the fact that only 248 participants were recruited (0.64% of the DARIS of 38,752 participants), the Trial Sequential Analysis program could not construct an interpretable figure and could not calculate Trial Sequential Analysis‐adjusted CIs.
Subgroup analysis
We could not perform two of the subgroup analyses because the risk of bias in the five trials was high, and because all trials included participants without refractory ascites (Subgroup analysis and investigation of heterogeneity).
Type of plasma expanders
The test for subgroup differences comparing the effects of each type of plasma expander showed no difference between the plasma expanders used (P = 0.99, I² = 0%) regarding other liver‐related complications: albumin versus the no plasma expander (RR 1.61, 95% CI 0.76 to 3.41; 158 participants; 3 trials; I2 = 0%; Analysis 1.4.1; Ginès 1988; García‐Compeán 1993; Luca 1995) and intravenous infusion of ascitic fluid versus the no plasma expander (RR 1.58, 95% CI 0.17 to 14.53; 90 participants; 1 trial; Analysis 1.4.2; Descos 1983).
Modality of paracentesis
The test for subgroup differences comparing the effects of the modality of paracentesis showed no difference (P = 0.97, I² = 0%; Analysis 2.3) regarding other liver‐related complications: participants with partial paracentesis (RR 1.63, 95% CI 0.57 to 4.66; 105 participants; 1 trial; Analysis 2.3.1; Ginès 1988) and participants with total paracentesis (RR 1.59, 95% CI 0.60 to 4.18; 143 participants; 3 trials; I2 = 0%; Analysis 2.3.2; Descos 1983; García‐Compeán 1993; Luca 1995).
Length of follow‐up
The test for subgroup differences comparing the effects of duration of follow‐up showed no difference between the trials with a short follow‐up and the trials with a long follow‐up (P = 0.97; I² = 0%; Analysis 3.3) regarding other liver‐related complications: in trials with a follow‐up up to one month (RR 1.59, 95% CI 0.60 to 4.18; 143 participants; 3 trials; I2 = 0%; Analysis 3.3.1; Descos 1983; García‐Compeán 1993; Luca 1995) and in the single trial with more than one month follow‐up (RR 1.63, 95% CI 0.57 to 4.66; 105 participants; Analysis 3.3.2; Ginès 1988).
For‐profit support
The test for subgroup differences comparing for‐profit support showed no difference between the two subgroups (P = 0.98, I2 = 0%; Analysis 4.3). We found no evidence of a difference in other liver‐related complications either in the subgroup of trials without for‐profit funding (RR 1.62, 95% CI 0.63 to 4.19; 213 participants; 3 trials; I2 = 0%; Analysis 4.3.1) or in the subgroup with the only trial without information on for‐profit funding (RR 1.59, 95% CI 0.54 to 4.67; 35 participants; 1 trial; Analysis 4.3.2).
Non‐serious adverse events
Non‐serious adverse events were reported in three trials; they included local hematoma, fistula, transient fever, hyperkalaemia, leakage, or oedema of the abdominal wall (Ginès 1988; García‐Compeán 1993; Luca 1995). The analysis result of these three trials showed no evidence of a difference between plasma expander and no plasma expander (RR 1.04, 95% CI 0.32 to 3.40; 158 participants; I² = 0%; Analysis 1.5). Including the trial with zero deaths in the Trial Sequential Analysis produced a comparable result (RR 1.04; 95% CI 0.32 to 3.40; P = 0.95).
We assessed the certainty of the evidence with GRADE as very low. We downgraded the evidence by four levels because all trials were at high risk of bias; and there was imprecision: there were few events and the CI included appreciable benefit and harm (summary of findings Table for the main comparison). The required information size was not reached (Table 1).
Trial Sequential Analysis was constructed based on the risk in the control group of 6.25%, a relative risk reduction of 10% with plasma expansion, a type I error of 2.00%, and a type II error of 20% (80% power). There was no diversity (D2 = 0%). The DARIS was 56,467 participants. Due to the fact that only 158 participants were recruited (which is 0.27% of the DARIS of 56,467 participants), the Trial Sequential Analysis program could not construct an interpretable figure and could not calculate Trial Sequential Analysis‐adjusted CIs.
Subgroup analysis
We could not perform three of the subgroup analyses because the risk of bias in the three trials was high, all the three trials included participants without refractory ascites, and non‐serious adverse events were reported only in the trial that used albumin.
Modality of paracentesis
The test for subgroup differences comparing the effects of modality of paracentesis showed no difference between the two subgroups (P = 0.98; I² = 0%; Analysis 2.4): plasma expanders versus no plasma expander in trials with partial paracentesis (RR 1.02, 95% CI 0.22 to 4.82; 105 participants; 1 trial; Analysis 2.4.1) and in trials with total paracentesis (RR 1.06, 95% CI 0.17 to 6.70; 53 participants; 2 trials; I² not applicable because 1/2 trials had 0 events; Analysis 2.4.2).
Length of follow‐up
The test for subgroup differences comparing the effects of duration of follow‐up showed no difference between the trials with a short follow‐up and the trials with more than one month follow‐up (P = 0.98, I² = 0%; Analysis 3.4): trials with a short follow‐up (RR 1.06, 95% CI 0.17 to 6.70; 53 participants; 2 trials; I2 not applicable; Analysis 3.4.1; García‐Compeán 1993; Luca 1995) and trials with a long follow‐up (RR 1.02, 95% CI 0.22 to 4.82; 105 participants; 1 trial; I2 not applicable; Analysis 3.4.2; Ginès 1988).
For‐profit support
The test for subgroup differences comparing for‐profit support showed no difference between the two subgroups (P = 0.98, I2 = 0%; Analysis 4.4). We found no evidence of difference in non‐serious adverse events either in the subgroup of trials without for‐profit funding (RR 1.02, 95% CI 0.22 to 4.82; 123 participants; 2 trials; I2 not applicable because 1/2 trial had 0 events; Analysis 4.4.1) or in the subgroup with the only trial without information on for‐profit funding (RR 1.06, 95% CI 0.17 to 6.70; 35 participants; Analysis 4.4.2).
Exploratory outcomes
Recurrence of ascites
Plasma expanders showed no evidence of a difference in effect on the recurrence of ascites (RR 1.30, 95% CI 0.49 to 3.42; 195 participants; 2 trials; I2 = 37%; Analysis 1.6).
We assessed the certainty of the evidence with GRADE as very low. We downgraded the evidence by three levels because the two trials were at high risk of bias; and there was imprecision: the required information size was not reached (Table 2; Table 3).
| Plasma expanders versus no plasma expander for people with cirrhosis and large ascites treated with abdominal paracentesis: exploratory outcomes | ||||||
| Patient or population: cirrhotic participants with large ascites treated by paracentesis Settings: specialised units in an intensive or semi‐intensive setting Intervention: plasma expander Comparison: no plasma expander | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Certainty of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No plasma expander | Plasma expander | |||||
| Recurrence of ascites mean follow‐up 126 days (30‐222) | Medium risk population | RR 1.30 (0.49 to 3.42) | 195 | ⊕⊝⊝⊝ | ||
| 155 per 1000 | 201 per 1000 | |||||
| Hypotension follow‐up 2 days | See comment | See comment | 23 (1) | There was a single trial with 0 events in each group. | ||
| Hyponatraemia mean follow‐up 57 days (1‐222) | Medium risk population | RR 0.53 (0.05 to 5.65) | 181 | ⊕⊝⊝⊝ | ||
| 130 per 1000 | 69 per 1000 | |||||
| * Assumed risk is the risk in comparison group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
1 Downgraded 3 levels because of within study risk of bias: all trials were at high risk of bias (‐2 levels); imprecision: the required information size as calculated by GRADE not reached (‐1 levels)
2 Downgraded 4 levels because of within study risk of bias: all trials were at high risk of bias (‐2 levels); high heterogeneity (67%) (‐1 level); imprecision: the required information size as calculated by GRADE was not reached (‐1 level)
| Comparison of imprecision evaluation with GRADE based on the GRADE Handbook, with GRADE based on authors' choice of plausible relative risk reduction and multiplicity correction, and according to our Trial Sequential Analysis with a similar choice of plausible relative risk reduction and multiplicity correction, in addition to considering the choice of meta‐analytic model and diversity | |||||||
| Outcome | Proportion in control group | Relative risk reduction | Alpha | Beta | Diversity | Required information size (OIS or DARIS) | Downgrading of evidence for imprecision based on required information size |
| Recurrence of ascites ‐‐ GRADE Handbook | 15.5% | 25% | 5% | 20% | Not used | 2444 | One level |
| Recurrence of ascites ‐‐ GRADE plausible RRR | 15.5% | 10% | 2% | 20% | Not used | 20,980 | One level |
| Recurrence of ascites ‐‐ TSA | 15.5% | 10% | 2% | 20% | 51% | 43,013 | One level |
| Hypotension ‐‐ GRADE Handbook (1) | |||||||
| Hypotension ‐‐ GRADE plausible RRR (1) | |||||||
| Hypotension ‐‐ TSA (1) | |||||||
| Hyponatraemia ‐‐ GRADE Handbook | 13% | 25% | 5% | 20% | Not used | 2996 | One level |
| Hyponatraemia ‐‐ GRADE plausible RRR | 13% | 10% | 2% | 20% | Not used | 25,712 | One level |
| Hyponatraemia ‐‐ TSA | 13% | 10% | 2% | 20% | 10% | 28,526 | One level |
(1) There was a single trial with 0 events in each group
OIS: optimal information size; DARIS: diversity‐adjusted required information size; RRR: relative risk reduction; TSA: Trial Sequential Analysis
Trial Sequential Analysis was constructed based on the risk of 15.5% in the control group, a relative risk reduction of 10% in the plasma expander group, a type I error of 2.00%, and a type II error of 20% (80% power). Diversity was present (D2 = 51%). The DARIS was 43,013 participants. Due to the fact that only 195 participants were recruited (which is 0.45% of the DARIS of 43,013 participants), the Trial Sequential Analysis program could not construct an interpretable figure and could not calculate Trial Sequential Analysis‐adjusted CIs.
Subgroup analysis
We did not conduct subgroup analysis because there were only two trials.
Hypotension
Only one of the trials reported that there was no occurrence of hypotension (Baik 2000) (Table 2; Table 3).
Hyponatraemia
Plasma expansion versus no plasma expansion showed no evidence of a difference in effect on the incidence of hyponatraemia (RR 0.53, 95% CI 0.05 to 5.65; 181 participants; 4 trials; I2 = 67%; Analysis 1.7). Including the trials with zero events in Trial Sequential Analysis produced a comparable result (RR 0.38, 95% CI 0.11 to 1.38; P = 0.15).
We assessed the certainty of the evidence with GRADE as very low. We downgraded the evidence by four levels because all trials were at high risk of bias; there was high heterogeneity; and there was imprecision: the required information size was not reached (Table 2; Table 3).
Trial Sequential Analysis was based on risk of 13% in the control group, a relative risk reduction of 10% with plasma expansion, a type I error of 2.00%, and a type II error of 20% (80% power). Diversity (D2) was 10%. The DARIS was 28,526 participants. Due to the fact that only 181 participants were recruited (which is 0.63% of the DARIS of 28,526 participants), the Trial Sequential Analysis program could not construct an interpretable figure and could not calculate Trial Sequential Analysis‐adjusted CIs.
Subgroup analyses
We could not perform three of the subgroup analysis because all the four trials were assessed at high risk of bias, included participants without refractory ascites, and used albumin.
Modality of paracentesis
The test for subgroup differences comparing the effects of modality of paracentesis showed a difference between the two subgroups (P = 0.08, I² = 67.3%; Analysis 2.5): trials using partial paracentesis (RR 0.19, 95% CI 0.04 to 0.80; 105 participants; 1 trial; Analysis 2.5.1; Ginès 1988) and trials using total paracentesis (RR 2.12, 95% CI 0.21 to 21.27; 76 participants; 3 trials; I2 not applicable because 2/3 trials had 0 events Analysis 2.5.2; García‐Compeán 1993; Luca 1995; Baik 2000).
Length of follow‐up
The test for subgroup differences comparing the effects of duration of follow‐up showed a difference between the two subgroups (P = 0.08, I² = 67.3% Analysis 3.5): trials with a short follow‐up (RR 2.12, 95% CI 0.21 to 21.27; 76 participants; 3 trials; I2 not applicable because 2/3 trials had 0 events; Analysis 3.5.1; García‐Compeán 1993; Luca 1995; Baik 2000) and trials with a long follow‐up (RR 0.19, 95% CI 0.04 to 0.80; 105 participants; Analysis 3.5.2; Ginès 1988).
For‐profit support
The test for subgroup differences comparing for‐profit support showed a difference between the two subgroups (P = 0.08, I2 = 67.3%; Analysis 4.5). Albumin versus no plasma expansion reduced hyponatraemia in the subgroup of trials without for‐profit funding (RR 0.19, 95% CI 0.04 to 0.80; 123 participants; 2 trials; I2 not applicable because 1/2 trial had 0 events; Analysis 4.5.1). No evidence of a difference was found in the subgroup of trials without information on for‐profit funding (RR 2.12, 95% CI 0.21 to 21.27; 58 participants; 2 trials; I2 not applicable because 1/2 trial had 0 events; Analysis 4.5.2).
Post‐paracentesis circulatory dysfunction
None of the included trials reported data on post‐paracentesis circulatory dysfunction.
Plasma expanders versus other plasma expanders
The trials compared different plasma expanders. Therefore, to achieve maximal homogeneity, we first analysed all the trials in which albumin was used as a control intervention, and then we analysed the trials in which both intervention groups used plasma expanders different from albumin.
Experimental plasma expanders versus albumin
Twenty‐one trials compared non‐albumin plasma expanders versus albumin (Planas 1990; Smart 1990; Bertrán 1991; Méndez 1991; Salerno 1991; Simonetti 1991; Bruno 1992; Fassio 1992; Hernández Pérez 1995; Ginès 1996; Graziotto 1997; Altman 1998; Kang 1998; Zhao 2000; García‐Compeán 2002; Degoricija 2003; Sola‐Vera 2003; Moreau 2006; Abdel‐Khalek 2010; Al Sebaey 2012; Khan 2015).
As one of these twenty‐one trials had three intervention groups, we performed the analysis splitting the trial as if there were two trials performed; i.e. polygeline versus albumin and dextran 70 versus albumin, using half of the participants in the albumin group for each of the comparisons (Ginès 1996). The trial by García‐Compeán 2002 did not report the number of participants allocated to the treatment groups, and, hence, we could not use their data for quantitative analysis. The trial by Degoricija 2003 did not report the number of events per intervention group, and, hence, we could not use it for quantitative analysis.
Primary outcomes
All‐cause mortality
Data on in‐hospital mortality were reported by five trials with albumin as the control intervention (Bruno 1992; Ginès 1996; Kang 1998; Sola‐Vera 2003; Khan 2015). In another five trials with a short follow‐up, mortality was not reported (Bertrán 1991; Méndez 1991; Hernández Pérez 1995; Altman 1998; Al Sebaey 2012).
Another nine trials provided mortality after discharge from hospital (Planas 1990; Smart 1990; Salerno 1991; Simonetti 1991; Fassio 1992; Graziotto 1997; Zhao 2000; Moreau 2006; Abdel‐Khalek 2010). Ginès and colleagues wrote that there was no difference in mortality between the two groups at follow‐up after discharge, but the trial did not report the number of events, and we received no reply from the trial authors to our data request (Ginès 1996).
There was no evidence of a difference in all‐cause mortality between the experimental plasma expanders group and the albumin group (RR 1.03, 95% CI 0.82 to 1.30; 1014 participants; 14 trials; I2 = 0%; Analysis 7.1; Figure 4). The intervention effect on all‐cause mortality did not change after inclusion of the two trials with zero deaths (RR 1.04; 95% CI 0.82 to 1.31; P = 0.75; D2 = 0%).
Funnel plot of comparison: 6 Experimental plasma expanders versus albumin, outcome: 6.1 All‐cause mortality.
We assessed the certainty of the evidence with GRADE as very low. We downgraded the evidence by four levels because all trials were at high risk of bias; there was imprecision: the required information size was not reached; there was evidence of publication bias (summary of findings Table 2; Table 4; Figure 4).
| Comparison of imprecision evaluation with GRADE based on the GRADE Handbook, with GRADE based on authors' choice of plausible relative risk reduction and multiplicity correction, and according to our Trial Sequential Analysis with a similar choice of plausible relative risk reduction and multiplicity correction, in addition to considering the choice of meta‐analytic model and diversity | |||||||
| Outcome | Proportion in control group | Relative risk reduction | Alpha | Beta | Diversity | Required information size (OIS or DARIS) | Downgrading of evidence for imprecision based on required information size |
| All‐cause mortality ‐‐ GRADE Handbook | 18.2% | 25% | 5% | 20% | Not used | 2030 | One level |
| All‐cause mortality ‐‐ GRADE plausible RRR | 18.2% | 10% | 2.5% | 20% | Not used | 16,415 | One level |
| All‐cause mortality ‐‐ TSA | 18.2% | 10% | 2.5% | 20% | 0% | 16,415 | One level |
| Serious adverse events ‐‐ GRADE Handbook | 1.8% | 25% | 5% | 20% | Not used | 24,032 | One level |
| Serious adverse events ‐‐ GRADE plausible RRR | 1.8% | 5% | 2.5% | 20% | Not used | 809,313 | One level |
| Serious adverse events ‐‐ TSA | 1.8% | 5% | 2.5% | 20% | 0% | 809,313 | One level |
| Health‐related quality of life ‐‐ GRADE Handbook | No data | ||||||
| Health‐related quality of life ‐‐ GRADE plausible RRR | No data | ||||||
| Health‐related quality of life ‐‐ TSA | No data | ||||||
| Refractory ascites ‐‐ GRADE Handbook | No data | ||||||
| Refractory ascites ‐‐ GRADE plausible RRR | No data | ||||||
| Refractory ascites ‐‐ TSA | No data | ||||||
| Renal impairment ‐‐ GRADE Handbook | 5% | 25% | 5% | 20% | Not used | 8404 | One level |
| Renal impairment ‐‐ GRADE plausible RRR | 5% | 10% | 2.00% | 20% | Not used | 72,650 | One level |
| Renal impairment ‐‐ TSA | 5% | 10% | 2.00% | 20% | 0% | 72,651 | One level |
| Other liver‐related complications ‐‐ GRADE Handbook | 18.5% | 25% | 5% | 20% | Not used | 1986 | One level |
| Other liver‐related complications ‐‐ GRADE plausible RRR | 18.5% | 10% | 2.00% | 20% | Not used | 16,990 | One level |
| Other liver‐related complications ‐‐ TSA | 18.5% | 10% | 2.00% | 20% | 0% | 16,992 | One level |
| Non‐serious adverse events ‐‐ GRADE Handbook | 2.5% | 25% | 5% | 20% | Not used | 16,904 | One level |
| Non‐serious adverse events ‐‐ GRADE plausible RRR | 2.5% | 10% | 2.00% | 20% | Not used | 148,922 | One level |
| Non‐serious adverse events ‐‐ TSA | 2.5% | 10% | 2.00% | 20% | 0% | 148,925 | One level |
OIS: optimal information size; DARIS: diversity‐adjusted required information size; RRR: relative risk reduction; TSA: Trial Sequential Analysis
Trial Sequential Analysis of this comparison was constructed on an all‐cause mortality of 18.2% in the albumin group, a relative risk reduction of 10% with the experimental plasma expanders, a type I error of 2.5%, and a type II error of 20% (80% power). There was no diversity (D2 = 0%). The DARIS was 16,415 participants. In Trial Sequential Analysis, the information fraction was too small to produce an inner wedge futility area. The cumulative Z curve (blue line) did not approach the monitoring boundaries (red lines) for benefit or harm or futility (Figure 5).
Experimental plasma expanders versus albumin ‐ 6.1 All‐cause mortality.
The diversity‐adjusted required information size of 16,415 participants was calculated based on a proportion of participants of 18.2% of participants dying in the control group; a relative risk reduction (RRR) of 10% in the plasma expander group; an alpha of 2.5%; a power of 80%; and a diversity of 0%.
The cumulative Z score did not cross borders for benefit, harm, or futility.
Subgroup analyses
We could not perform subgroup analysis of trials in terms of all‐cause mortality according to their risk of bias because all the trials were assessed at high risk.
Type of plasma expanders
The test for subgroup differences comparing the effects of distinct plasma expanders showed no difference between the six subgroups (P = 0.89, I² = 0%; Analysis 7.1).
The type of plasma expander compared with albumin showed no evidence of difference in effect on all‐cause mortality: dextran (RR 1.28, 95% CI 0.79 to 2.06; 271 participants; 3 trials; I2 = 0%; Analysis 7.1.1; Planas 1990; Fassio 1992; Ginès 1996); hydroxyethyl starch (RR 1.16, 95% CI 0.45 to 3.02; 147 participants; 2 trials; I2 not applicable because 1 out of 2 trials had 0 events; Analysis 7.1.2; Kang 1998; Abdel‐Khalek 2010); polygeline (RR 1.12, 95% CI 0.67 to 1.89; 319 participants; 4 trials; I2 = 0%; Analysis 7.1.3; Salerno 1991; Ginès 1996; Moreau 2006; Khan 2015); intravenous infusion of ascites (RR 0.89, 95% CI 0.61 to 1.31; 137 participants; 4 trials; I2 = 0%; Analysis 7.1.4; Smart 1990; Simonetti 1991; Bruno 1992; Graziotto 1997); mannitol (RR 0.88, 95% CI 0.47 to 1.66; Analysis 7.1.5; Zhao 2000); and crystalloids (RR 1.06, 95% CI 0.07 to 16.26; Analysis 7.1.6; Sola‐Vera 2003).
Refractory ascites
The test for subgroup differences comparing the effects of refractory ascites showed no difference between the two subgroups (P = 0.59, I² = 0%; Analysis 8.1): trials including participants without refractory ascites (RR 1.15, 95% CI 0.80 to 1.66; 723 participants; 9 trials; I2 = 0%; Analysis 8.1.1) and trials including participants with refractory ascites (RR 1.01, 95% CI 0.75 to 1.37; 291 participants; 5 trials; I2 = 0%; Analysis 8.1.2).
Modality of paracentesis
The test for subgroup differences comparing the effects of modality of paracentesis showed no difference between the two subgroups (P = 0.73, I² = 0%; Analysis 9.1). We found no evidence of a difference in all‐cause mortality either in the partial paracentesis subgroup (RR 0.98, 95% CI 0.59 to 1.65; 109 participants; 2 trials; I2 = 0%; Analysis 9.1.1) or in the total paracentesis subgroup (RR 1.09, 95% CI 0.84 to 1.41; 905 participants; 12 trials; I2 = 0%; Analysis 9.1.2).
Length of follow‐up
The test for subgroup differences comparing the effect of length of follow‐up showed no difference between the two subgroups (P = 0.48, I² = 0%; Analysis 10.1). In the trials with a short follow‐up, we found a RR 1.59, 95% CI 0.47 to 5.33; 458 participants; 5 trials; I2 = 0% (Analysis 10.1.1); and in the trials with a long follow‐up, we found a RR 1.02, 95% CI 0.80 to 1.29; 556 participants; 9 trials; I2 = 0% (Analysis 10.1.2).
For‐profit support
The test for subgroup differences comparing for‐profit support showed no difference (P = 0.41, I2 = 0%; Analysis 11.1). We found no evidence of a difference in all‐cause mortality either in the trials without for‐profit funding (RR 1.19, 95% CI 0.79 to 1.81; 357 participants; 6 trials; I2 = 0%; Analysis 11.1.1) or in the trials with or unknown for‐profit funding (RR 0.97, 95% CI 0.73 to 1.28; 657 participants; 8 trials; I2 = 0%; Analysis 11.1.2).
Sensitivity analysis
Hypothesising the best‐worst scenario, mortality was increased by the other plasma expanders in comparison with albumin (RR 1.29, 95% CI 1.04 to 1.60; 1016 participants; 14 trials; I2 = 0%; Analysis 12.1). The worst‐best scenario analysis showed no evidence of a difference between other plasma expanders versus albumin (RR 0.99, 95% CI 0.96 to 1.03; 1016 participants; 14 trials; I2 = 8%; Analysis 13.1).
Serious adverse events
Two trials reported data on serious adverse events. There was no evidence of a difference between other plasma expanders versus albumin in serious adverse events (Moreau 2006; Khan 2015) (RR 0.89, 95% CI 0.10 to 8.30; 118 participants; 2 trials; I2 = 0%; Analysis 7.2).
We assessed the certainty of the evidence with GRADE as very low. We downgraded the evidence by four levels because: all trials were at high risk of bias; and there was imprecision: there were few events and the CI included appreciable benefit and harm (summary of findings Table 2). The optimal information size as calculated by GRADE was not reached (Table 4).
The Trial Sequential Analysis of this comparison was based on a risk of 1.8% in the control group, a relative risk reduction of 5% with experimental plasma expanders, a type I error of 2.5%, and a type II error of 20% (80% power). There was no diversity (D2 = 0%). The DARIS was 809,313 participants. Due to the fact that only 118 participants were recruited (which is 0.01% of the DARIS of 809,313 participants), the Trial Sequential Analysis program could not construct an interpretable figure and could not calculate Trial Sequential Analysis‐adjusted CIs.
Subgroup analyses
We could not perform subgroup analysis of trials according to their risk of bias, presence of refractory ascites, type of plasma expanders, modality of paracentesis, or for‐profit funding because both trials included participants with and without refractory ascites, used polygeline, performed total paracentesis, and were without for‐profit funding.
Length of follow‐up
The subgroup analysis comparing the effects of length of follow‐up showed no differences (P = 0.39, I² = 0%; Analysis 10.2): in the single trial with a short follow‐up (Khan 2015) (RR 0.33, 95% CI 0.01 to 7.81; 50 participants; Analysis 10.2.1) and in the single trial with a long follow‐up (Moreau 2006) (RR 2.38, 95% CI 0.10 to 56.53; 68 participants; Analysis 10.2.2).
Health‐related quality of life
None of the included trials assessed the health‐related quality of life.
Secondary outcomes
Refractory ascites
None of the included trials comparing a plasma expander versus albumin reported data on refractory ascites.
Renal impairment
Seventeen trials reported data on renal impairment (Planas 1990; Smart 1990; Bertrán 1991; Salerno 1991; Simonetti 1991; Bruno 1992; Fassio 1992; Hernández Pérez 1995; Ginès 1996; Graziotto 1997; Altman 1998; Kang 1998; Zhao 2000; Sola‐Vera 2003; Moreau 2006; Abdel‐Khalek 2010; Khan 2015). There was no evidence of a difference between experimental plasma expanders versus albumin in renal impairment (RR 1.17, 95% CI 0.71 to 1.91; 1107 participants; 17 trials; I2 = 0%; Analysis 7.3; Figure 6). Including the six trials with 0 events in Trial Sequential Analysis, renal impairment did not change significantly (RR 1.25, 95% CI 0.65 to 2.07; P = 0.39, D2 = 0%) (Bruno 1992; Graziotto 1997; Altman 1998; Kang 1998; Zhao 2000; Khan 2015).
Funnel plot of comparison: 6 Experimental plasma expanders versus albumin, outcome: 6.3 Renal impairment.
We assessed the certainty of the evidence with GRADE as very low. We downgraded the evidence by four levels because all trials were at high risk of bias; the required information size was not reached; and the funnel plot suggested publication bias (summary of findings Table 2; Table 4; Figure 6).
Trial Sequential Analysis of this comparison was based on a renal impairment proportion of 5% in the albumin group, a relative risk reduction of 10% with experimental plasma expanders, a type I error of 2.00%, and a type II error of 20% (80% power). There was no diversity (D2 = 0%). The DARIS was 72,651 participants. The Trial Sequential Analysis program could not construct an interpretable figure due to too little information (1.52%) (figure not shown) and Trial Sequential Analysis‐adjusted CIs could not be calculated.
Subgroup analysis
We could not perform subgroup analysis of trials in terms of renal impairment according to their risk of bias because all the trials were at high risk.
Type of plasma expanders
The test for subgroup differences comparing the effects of different plasma expanders showed no difference (P = 0.88, I² = 0%; Analysis 7.3): trials assessing versus albumin: dextran (RR 0.85, 95% CI 0.34 to 2.08; 304 participants; 5 trials; I2 = 0%; Analysis 7.3.1), hydroxyethyl starch (RR 1.01, 95% CI 0.06 to 15.90; 207 participants; 3 trials; I2 not applicable because 2/3 trials had 0 events; Analysis 7.3.2), polygeline (RR 1.53, 95% CI 0.70 to 3.38; 319 participants; 4 trials; I2 = 0%; Analysis 7.3.3), intravenous infusion of ascites (RR 0.90, 95% CI 0.22 to 3.62; 137 participants; 4 trials; I2 = 24%; Analysis 7.3.4), and crystalloids (RR 1.59, 95% CI 0.28 to 8.93; 72 participants; 1 trial; Analysis 7.3.6). No events were observed in the only trial in which mannitol was assessed (Zhao 2000) (Analysis 7.3.5).
Refractory ascites
The test for subgroup differences comparing the trials including participants without refractory ascites to the trials with participants with refractory ascites showed no difference (P = 0.69, I² = 0%; Analysis 8.2): trials including participants without refractory ascites (RR 1.24, 95% CI 0.70 to 2.20; 816 participants; 12 trials; I2 = 0%; Analysis 8.2.1) and trials including participants with refractory ascites (RR 0.98, 95% CI 0.37 to 2.65; 291 participants; 5 trials; I2 = 0%; Analysis 8.2.2).
Modality of paracentesis
The test for subgroup differences comparing different modality of paracentesis showed no difference (P = 0.99, I² = 0%; Analysis 9.2): trials in which partial paracentesis was used (RR 1.05, 95% CI 0.07 to 15.68; 169 participants; 3 trials; I2 not applicable because 2/3 trials had 0 events; Analysis 9.2.1) and trials in which total paracentesis was used (RR 1.04, 95% CI 0.59 to 1.84; 870 participants; 13 trials; I2 = 0%; Analysis 9.2.2).
Length of follow‐up
The test for subgroup differences comparing different lengths of follow‐up showed no difference between subgroups (P = 0.98, I² = 0%; Analysis 10.3): trials with a follow‐up up to one month (RR 1.13, 95% CI 0.56 to 2.25; 551 participants; 8 trials; I2 = 0%; Analysis 10.3.1) and trials with more than one month follow‐up (RR 1.14, 95% CI 0.58 to 2.22; 556 participants; 9 trials; I2 = 0%; Analysis 10.3.2).
For‐profit support
The test for subgroup differences comparing for‐profit support showed no difference between the two subgroups (P = 0.40, I2 = 0%; Analysis 11.2). We found no evidence of a difference in renal impairment either in the subgroup of trials without for‐profit funding (RR 1.46, 95% CI 0.72 to 2.97; 357 participants; 6 trials; I2 = 0%; Analysis 11.2.1) or in the subgroup of trials with or unknown for‐profit funding (RR 0.95, 95% CI 0.48 to 1.90; 750 participants; 11 trials; I2 = 0%; Analysis 11.2.2).
Other liver‐related complications
Other liver‐related complications were reported In 16 trials (Planas 1990; Smart 1990; Bertrán 1991; Salerno 1991; Simonetti 1991; Bruno 1992; Fassio 1992; Hernández Pérez 1995; Ginès 1996; Altman 1998; Kang 1998; Zhao 2000; Sola‐Vera 2003; Moreau 2006; Abdel‐Khalek 2010; Khan 2015). There was no evidence of a difference between experimental plasma expanders versus albumin in other liver‐related complications (RR 1.10, 95% CI 0.82 to 1.48; 1083 participants; 16 trials; I2 = 19%; Analysis 7.4; Figure 7). The effect of the interventions on the occurrence of other liver‐related complications did not change by including the four trials with zero events (Bruno 1992; Hernández Pérez 1995; Kang 1998; Khan 2015) (RR 1.17, 95% CI 0.92 to 1.48; P = 0.20; D2 = 0%).
Funnel plot of comparison: 6 Experimental plasma expanders versus albumin, outcome: 6.4 Other liver‐related complications.
We assessed the certainty of the evidence for this outcome as very low. We downgraded the evidence by four levels because all trials were at high risk of bias; there was imprecision: the required information size was not reached; and the funnel plot suggested publication bias (summary of findings Table 2; Table 4; Figure 7).
Trial Sequential Analysis of this comparison was based on an incidence of other liver‐related complications of 18.5% in the albumin group, a relative risk reduction of 10% with experimental plasma expanders, a type I error of 2.00%, and a type II error of 20% (80% power). There was no diversity (D2 = 0%). The diversity‐adjusted required information size was 16,992 participants. In Trial Sequential Analysis, the accrued information fraction was too small to produce the inner wedge futility area. The cumulative Z curve (blue line) did not reach the monitoring boundary (red line) suggesting that the results were not stable to adjustments for sparse data and multiple testing (Figure 8).
Experimental plasma expander versus albumin ‐ 6.4 Other liver‐related complications.
The diversity‐adjusted required information size of 16,992 participants was calculated based on a proportion of participants of 18.5% with other liver‐related complications in the control group; a relative risk reduction (RRR) of 10% in the plasma expander group; an alpha of 2.00%; a power of 80%; and a diversity of 0%.
The cumulative Z score did not cross borders for benefit, harm, or futility.
Subgroup analysis
We could not perform subgroup analysis of trials according to the risk of bias because all the trials were assessed at high risk.
Type of plasma expanders
The test for subgroup differences comparing the effects of different plasma expanders versus albumin showed a difference (P = 0.09, I² = 47.9%; Analysis 7.4): dextran (RR 1.49, 95% CI 0.98 to 2.28; 304 participants; 5 trials; I2 = 0%; Analysis 7.4.1); hydroxyethyl starch (RR 1.13, 95% CI 0.69 to 1.85; 207 participants; 3 trials; I2 = 0%; Analysis 7.4.2); polygeline (RR 0.91, 95% CI 0.43 to 1.93; 319 participants; 4 trials; I2 = 46%; Analysis 7.4.3); mannitol (RR 1.45, 95% CI 0.61 to 3.44; 68 participants; 1 trial; Analysis 7.4.5); and crystalloids (RR 1.06, 95% CI 0.16 to 7.10; 72 participants; 1 trial; Analysis 7.4.6)). Intravenous infusion of ascites reduced significantly other liver‐related complications in comparison with albumin (RR 0.23, 95% CI 0.07 to 0.73; 113 participants; 3 trials; I2 = 0%; Analysis 7.4.4).
Refractory ascites
The test for subgroup differences comparing separately the trials including participants without refractory ascites to trials including participants with refractory ascites showed a difference (P = 0.005, I² = 87%; Analysis 8.3): trials including participants without refractory ascites (RR 1.36, 95% CI 1.03 to 1.80; 766 participants; 12 trials; I2 = 0%; Analysis 8.3.1) and in trials including participants with refractory ascites (RR 0.64, 95% CI 0.41 to 1.00; 267 participants; 4 trials; I2 = 61%; Analysis 8.3.2).
Modality of paracentesis
The test for subgroup differences comparing the effects of the experimental plasma expanders versus albumin in people treated by total compared to partial paracentesis showed no difference (P = 0.26, I² = 20.9%; Analysis 9.3): trials with partial paracentesis (RR 1.54, 95% CI 0.76 to 3.11; 169 participants; 3 trials; I2 = 0%; Analysis 9.3.1) and trials with total paracentesis (RR 0.98, 95% CI 0.67 to 1.42; 864 participants; 13 trials; I2 = 37%); Analysis 9.3.2)).
Length of follow‐up
The test for subgroup differences comparing separately the trials with a short follow‐up to the trials with a long follow‐up showed no difference (P = 0.66, I² = 0%; Analysis 10.4): trials with up to one month follow‐up (RR 1.17, 95% CI 0.64 to 2.16; 501 participants; 7 trials; I2 = 0%; Analysis 10.4.1) and trials with more than one month follow‐up (RR 0.99, 95% CI 0.65 to 1.53; 532 participants; 8 trials; I2 = 50%; Analysis 10.4.2).
For‐profit support
The test for subgroup differences comparing for‐profit support showed no difference between the two subgroups (P = 0.20, I2 = 40.3%; Analysis 11.3). Experimental plasma expanders versus albumin led to more participants with other liver‐related complications in the subgroup of trials without for‐profit funding (RR 1.42, 95% CI 1.03 to 1.97; 357 participants; 6 trials; I2 = 0%; Analysis 11.3.1). We found no evidence of a difference in the subgroup of trials with or unknown for‐profit funding (RR 1.02, 95% CI 0.69 to 1.50; 726 participants; 10 trials; I2 = 7%; Analysis 11.3.2).
Non‐serious adverse events
Non‐serious adverse events were reported in 14 trials (Planas 1990; Smart 1990; Salerno 1991; Simonetti 1991; Bruno 1992; Hernández Pérez 1995; Ginès 1996; Graziotto 1997; Altman 1998; Kang 1998; Zhao 2000; Sola‐Vera 2003; Moreau 2006; Abdel‐Khalek 2010). There was no evidence of a difference between the experimental plasma expanders group versus the albumin group in other liver‐related complications (RR 1.37, 95% CI 0.66 to 2.85; 977 participants; 14 trials; I2 = 0%; Analysis 7.5; Figure 9).
Funnel plot of comparison: 6 Experimental plasma expanders versus albumin, outcome: 6.5 Non‐serious adverse events.
Including the four trials with zero events produced a similar result (RR 0.92, 95% CI 0.36 to 2.35; P = 0.85; D2 = 0%) (Hernández Pérez 1995; Ginès 1996; Zhao 2000; Sola‐Vera 2003).
We assessed the level of certainty of the evidence for this outcome as very low. We downgraded the evidence by three levels because all trials were at high risk of bias; and there was imprecision: the required information size was not reached (summary of findings Table 2; Table 4). There was no publication bias (Figure 9).
Trial Sequential Analysis of this comparison was based on a non‐serious adverse event proportion of 2.5% in the albumin group, a relative risk reduction of 10% with experimental plasma expanders, a type I error of 2.00%, and a type II error of 20% (80% power). There was no diversity (D2 = 0%). The diversity‐adjusted required information size was 148,925 participants. Due to the fact that only 977 participants were recruited (which is 0.65% of the diversity‐adjusted required information size of 148,925 participants), the Trial Sequential Analysis program could not construct an interpretable figure and could not calculate the Trial Sequential Analysis‐adjusted confidence intervals.
Subgroup analysis
We could not perform subgroup analysis of trials according to the risk of bias because all the trials were at high risk.
Type of plasma expanders
The test for subgroup differences comparing the effects of different plasma expanders versus albumin showed no difference (P = 0.66, I² = 0%; Analysis 7.5): trials assessing dextran (RR 0.48, 95% CI 0.04 to 5.08; 246 participants; 3 trials; I2 not applicable because 2/3 trials had 0 events; Analysis 7.5.1); hydroxyethyl starch (RR 2.26, 95% CI 0.66 to 7.71; 207 participants; 3 trials; I2 = 0%; Analysis 7.5.2); polygeline (RR 0.91, 95% CI 0.15 to 5.47; 277 participants; 3 trials; I2 = 0%; Analysis 7.5.3); intravenous infusion of ascites (RR 1.54, 95% CI 0.41 to 5.71; 137 participants; 4 trials; I2 = 14%; Analysis 7.5.4). No events were observed in the mannitol and in the crystalloids subgroups.
Refractory ascites
The test for subgroup differences comparing separately the trials including participants without refractory ascites to trials including participants with refractory ascites showed no difference (P = 0.88, I² = 0%; Analysis 8.4): trials with participants without refractory ascites (RR 1.47, 95% CI 0.49 to 4.36; 686 participants; 10 trials; I2 = 0%; Analysis 8.4.1) and trials with participants with refractory ascites (RR 1.30, 95% CI 0.49 to 3.47; 291 participants; 5 trials; I2 = 0%; Analysis 8.4.2).
Modality of paracentesis
The test for subgroup differences comparing the effects of experimental plasma expanders versus albumin in participants treated by partial or total paracentesis showed no difference (P = 0.21, I2 = 37.3%; Analysis 9.4): trials in which partial paracentesis was performed (RR 8.50, 95% CI 0.46 to 157.71; 98 participants; 2 trials; I2 not applicable because 1/2 trials had 0 events; Analysis 9.4.1) and trials in which total paracentesis was performed (RR 1.22, 95% CI 0.57 to 2.58; 879 participants; 13 trials; I2 = 0%; Analysis 9.4.2).
Length of follow‐up
The test for subgroup differences comparing the effects of experimental plasma expanders versus albumin in participants with a short (up to one month) follow‐up compared to a long follow‐up showed no difference (P = 0.26, I² = 22.6%; Analysis 10.5): trials with a short follow‐up (RR 2.20, 95% CI 0.73 to 6.59; participants 484; 6 trials; I2 = 0; Analysis 10.5.1) and trials with a long follow‐up (RR 0.97, 95% CI 0.41 to 2.32; 493 participants; 8 trials; I2 = 0%; Analysis 10.5.2).
For‐profit support
The test for subgroup differences comparing for‐profit support showed no difference between the two subgroups (P = 0.27, I2 = 18.2%; Analysis 11.4). We found no evidence of a difference in non‐serious adverse events either in the subgroup of trials without for‐profit funding (RR 0.62, 95% CI 0.12 to 3.05; 274 participants; 4 trials; I2 = 0%; Analysis 11.4.1) or in the subgroup of trials with or unknown for‐profit funding (RR 1.70, 95% CI 0.75 to 3.85; 703 participants; 10 trials; I2 = 0%; Analysis 11.4.2).
Exploratory outcomes
Recurrence of ascites
Recurrence of ascites was reported in 12 trials (Planas 1990; Smart 1990; Salerno 1991; Simonetti 1991; Fassio 1992; Méndez 1991; Hernández Pérez 1995; Altman 1998; Zhao 2000; Sola‐Vera 2003; Moreau 2006; Abdel‐Khalek 2010). Experimental plasma expanders had no effect in the recurrence of ascites in comparison with albumin (RR 1.14, 95% CI 0.96 to 1.36; 700 participants; 12 trials; I2 = 8%; Analysis 7.6; Figure 10).
Funnel plot of comparison: 6 Experimental plasma expanders versus albumin, outcome: 6.6 Recurrence of ascites.
We assessed the level of certainty of the evidence with GRADE as very low. We downgraded the evidence by three levels because all trials were at high risk of bias; and there was imprecision: the required information size was not reached (Table 5; Table 6). There was no evidence of publication bias (Figure 10).
| Plasma expanders versus albumin for people with cirrhosis and large ascites treated with abdominal paracentesis: exploratory outcomes | ||||||
| Patient or population: cirrhotic participants with large ascites treated by paracentesis Settings: specialised units in an intensive or semi‐intensive setting Intervention: all plasma expanders except albumin Comparison: albumin | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Certainty of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Albumin | Experimental plasma expanders | |||||
| Recurrence of ascites mean follow‐up 169 days (5‐638) | Medium risk population | RR 1.14 (0.96 to 1.36) | 700 | ⊕⊝⊝⊝ | ||
| 363 per 1000 | 412 per 1000 | |||||
| Hypotension follow‐up 6 days | 88 per 1000 | 239 per 1000 | RR 2.71 (1.13 to 6.50) | 135 | Certainty of the evidence not assessed | |
| Hyponatraemia mean follow‐up 174 days (3‐638) | Medium risk population | RR 1.49 (1.03 to 2.14) | 1107 | ⊕⊝⊝⊝ | ||
| 73 per 1000 | 108 per 1000 | |||||
| Post‐paracentesis circulatory dysfunction mean follow‐up 100 days (6‐288) | Medium risk population | RR 1.98 (1.31 to 2.99) | 432 | ⊕⊝⊝⊝ | ||
| 148 per 1000 | 294 per 1000 | |||||
| * Assumed risk is the risk in comparison group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
1 Downgraded 3 levels because of within study risk of bias: all trials were at high risk of bias (‐2 levels); imprecision: required information size as calculated by GRADE not reached (‐1 level)
2 Not evaluated because there was only one trial
3 Downgraded 4 levels because of within study risk of bias: all trials were at high risk of bias (‐2 levels); imprecision: the required information size as calculated by GRADE was not reached (‐1 level); publication bias(‐1 level)
4 Downgraded 3 levels because of within study risk of bias: all trials were at high risk of bias (‐2 levels); imprecision: the required information size as calculated by GRADE was not reached (‐1 level)
| Comparison of imprecision evaluation with GRADE based on the GRADE Handbook, with GRADE based on authors' choice of plausible relative risk reduction and multiplicity correction, and according to our Trial Sequential Analysis with a similar choice of plausible relative risk reduction and multiplicity correction, in addition to considering the choice of meta‐analytic model and diversity | |||||||
| Outcome | Proportion in control group | Relative risk reduction | Alpha | Beta | Diversity | Required information size (OIS or DARIS) | Downgrading of evidence for imprecision based on required information size |
| Recurrence of ascites ‐‐ GRADE Handbook | 36.3% | 25% | 5% | 20% | Not used | 824 | One level |
| Recurrence of ascites ‐‐ GRADE plausible RRR | 36.3% | 10% | 2% | 20% | Not used | 6882 | One level |
| Recurrence of ascites ‐‐ TSA | 36.3% | 10% | 2% | 20% | 3% | 7104 | One level |
| Hypotension ‐‐ GRADE Handbook | 8.8% | 25% | 5% | 20% | Not used | 4608 | One level |
| Hypotension ‐‐ GRADE plausible RRR | 8.8% | 10% | 2% | 20% | Not used | 39,712 | One level |
| Hypotension ‐‐ TSA (1) | |||||||
| Hyponatraemia ‐‐ GRADE Handbook | 7.3% | 25% | 5% | 20% | Not used | 5602 | One level |
| Hyponatraemia ‐‐ GRADE plausible RRR | 7.3% | 10% | 2% | 20% | Not used | 48,618 | One level |
| Hyponatraemia ‐‐ TSA | 7.3% | 10% | 2% | 20% | 0% | 48,620 | One level |
| Post‐paracentesis circulatory dysfunction ‐‐ GRADE Handbook | 14.8% | 25% | 5% | 20% | Not used | 2584 | One level |
| Post‐paracentesis circulatory dysfunction ‐‐ GRADE plausible RRR | 14.8% | 10% | 2% | 20% | Not used | 22,144 | One level |
| Post‐paracentesis circulatory dysfunction ‐‐ TSA | 14.8% | 10% | 2% | 20% | 0% | 22,146 | One level |
(1) TSA non calculated because there was only one trial
OIS: optimal information size; DARIS: diversity‐adjusted required information size; RRR: relative risk reduction; TSA: Trial Sequential Analysis
Trial Sequential Analysis of this comparison was based on a recurrence of ascites proportion of 36.3% in the albumin group, a relative risk reduction of 10% with experimental plasma expanders, a type I error of 2.00%, and a type II error of 20% (80% power). The diversity (D2) was 3%. The diversity‐adjusted required information size was 7104 participants. In Trial Sequential Analysis, the accrued information fraction was too small to produce an inner wedge futility area. The cumulative Z curve (blue line) did not approach the monitoring boundaries (red lines) for benefit or harm, demonstrating too few data (Figure 11).
Experimental plasma expanders versus albumin ‐ 6.6 Recurrence of ascites.
The diversity‐adjusted required information size of 7104 participants was calculated based on a proportion of participants of 36.3% of participants suffering recurrence of ascites in the control group; a relative risk reduction (RRR) of 10% in the plasma expander group; an alpha of 2%; a power of 80%; and a diversity of 3%.
The cumulative Z score did not cross borders for benefit, harm, or futility.
Subgroup analysis
We could not perform subgroup analysis of trials according to the risk of bias because all the trials were at high risk of bias.
Type of plasma expanders
The test for subgroup differences comparing the effects of different plasma expanders versus albumin showed no differences between subgroups (P = 0.56, I² = 0%; Analysis 7.6): trials assessing dextran (RR 0.85, 95% CI 0.53 to 1.37; 145 participants; 3 trials; I2 = 0%; Analysis 7.6.1); polygeline (RR 1.03, 95% CI 0.69 to 1.54; 122 participants; 2 trials; I2 = 38%; Analysis 7.6.3); intravenous infusion of ascites (RR 1.03, 95% CI 0.46 to 2.34; 78 participants; 2 trials; I2 = 79%; Analysis 7.6.4); mannitol (RR 0.90, 95% CI 0.26 to 3.07; 68 participants; Analysis 7.6.5); and crystalloids (RR 1.16, 95% CI 0.57 to 2.39; 72 participants; Analysis 7.6.6). Hydroxyethyl starch increased the risk of recurrence of ascites in comparison with albumin (RR 1.49, 95% CI 1.03 to 2.15; 215 participants; 3 trials; I2 = 0%; Analysis 7.6.2).
Refractory ascites
The test for subgroup differences comparing the trials including participants without refractory ascites to trials including participants with refractory ascites did not show differences (P = 0.70, I² = 0%; Analysis 8.5): participants without refractory ascites (RR 1.10, 95% CI 0.90 to 1.35; 487 participants; 9 trials; I2 = 0%; Analysis 8.5.1) and participants with refractory ascites (RR 1.19, 95% CI 0.86 to 1.66; 235 participants; 4 trials; I2 = 30%; Analysis 8.5.2).
Modality of paracentesis
The test for subgroup difference comparing the effects of experimental plasma expanders versus albumin in people treated by partial or total paracentesis showed no differences (P = 0.60, I² = 0%; Analysis 9.5): participants treated by partial paracentesis (RR 1.28, 95% CI 0.72 to 2.26; 169 participants; 3 trials; I2 = 0%, Analysis 9.5.1) and participants treated by total paracentesis (RR 1.09, 95% CI 0.91 to 1.30; 533 participants; 9 trials; I2 = 8%; Analysis 9.5.2).
Length of follow‐up
The test for subgroup differences comparing the effects of experimental plasma expanders versus albumin in participants with a short (up to one month) follow‐up compared to a long (more than one month) follow‐up showed a difference between the subgroups (P = 0.03, I² = 77.9%; Analysis 10.6): trials with a short follow‐up (RR 2.07, 95% CI 1.12 to 3.83; 96 participants; 3 trials; I2 = 0%; Analysis 10.6.1) and trials with a follow‐up longer than one month (RR 1.03, 95% CI 0.86 to 1.24; 606 participants; 9 trials; I2 = 0%; Analysis 10.6.2).
For‐profit support
The test for subgroup differences comparing for‐profit support showed no difference between the two subgroups (P = 0.87, I2 = 0%; Analysis 11.5). We found no evidence of difference in recurrence of ascites either in the subgroup of trials without for‐profit funding (RR 1.16, 95% CI 0.96 to 1.42; 307 participants; 5 trials; I2 = 0%; Analysis 11.5.1) or in the subgroup of trials with or unknown for‐profit funding (RR 1.13, 95% CI 0.79 to 1.60; 393 participants; 7 trials; I2 = 28%; Analysis 11.5.2).
Hypotension
One trial mentioned clinical hypotension that was more frequent in the hydroxyethyl starch group (16/67 participants, 24%) than in the albumin group (6/68 participants, 8%) (P = 0.02) (Abdel‐Khalek 2010) (Table 5; Table 6).
Hyponatraemia
Hyponatraemia was reported in seventeen trials (Planas 1990; Smart 1990; Bertrán 1991; Salerno 1991; Simonetti 1991; Bruno 1992; Fassio 1992; Hernández Pérez 1995; Ginès 1996; Graziotto 1997; Altman 1998; Kang 1998; Zhao 2000; Sola‐Vera 2003; Moreau 2006; Abdel‐Khalek 2010; Khan 2015). Hyponatraemia was more frequent in the experimental plasma expander group than in the albumin group (RR 1.49, 95% CI 1.03 to 2.14; 1107 participants; 17 trials; I2 = 0%; Analysis 7.7; Figure 12).
Funnel plot of comparison: 6 Experimental plasma expanders versus albumin, outcome: 6.7 Hyponatraemia.
Including the five trials with zero events (Simonetti 1991; Graziotto 1997; Kang 1998; Zhao 2000; Khan 2015), the result was similar (RR 1.45, 95% CI 1.00 to 2.09, P = 0.05).
We assessed the certainty of the evidence for this outcome as very low. We downgraded the evidence by four levels because all trials were at high risk of bias; there was imprecision: the required information size was not reached; and there was publication bias (Table 5; Table 6; Figure 12).
Trial Sequential Analysis of this comparison was based on a hyponatraemia proportion of 7.3% in the albumin group, a relative risk reduction of 10% with experimental plasma expanders, a type I error of 2.00%, and a type II error of 20% (80% power). There was no diversity (D2 = 0%). The diversity‐adjusted required information size was 48,620 participants. The Trial Sequential Monitoring boundary could not be constructed due to too little information (2.28%) (figure not shown).
Subgroup analysis
We could not perform subgroup analysis of trials according to the risk of bias because all the trials were at high risk of bias.
Type of plasma expanders
The test for subgroup differences comparing the effects of different plasma expanders showed no difference between the subgroups (P = 0.94, I² = 0%; Analysis 7.7). No evidence of a difference in hyponatraemia was reported in the trials assessing dextran (RR 1.44, 95% CI 0.81 to 2.58; 304 participants; 5 trials; I2 = 0%; Analysis 7.7.1), hydroxyethyl starch (RR 1.87, 95% CI 0.40 to 8.69; 207 participants; 3 trials; I2 = 0%; Analysis 7.7.2), polygeline (RR 1.43, 95% CI 0.83 to 2.46; 319 participants; 4 trials; I2 = 0%; Analysis 7.7.3), intravenous infusion of ascites (RR 1.03, 95% CI 0.15 to 6.93; 137 participants; 4 trials; I2 = 0%; Analysis 7.7.4), and crystalloids (RR 2.64, 95% CI 0.55 to 12.75; 72 participants; Analysis 7.7.6) versus albumin. No events occurred in the mannitol trial (Zhao 2000) (Analysis 7.7.5).
Refractory ascites
The test for subgroup differences comparing the trials including participants without refractory ascites to the trials including participants with refractory ascites did not show a difference between the subgroups (P = 0.74, I² = 0%; Analysis 8.6). In the trials including participants without refractory ascites, the experimental plasma expanders increased the risk of hyponatraemia in comparison with albumin (RR 1.53, 95% CI 1.03 to 2.27; P = 0.04; 816 participants; 13 trials; I2 = 0%; Analysis 8.6.1). In the trials including participants with refractory ascites, no differences between the experimental plasma expanders and albumin were shown (RR 1.29, 95% CI 0.51 to 3.26; I2 = 0%; 291 participants; 5 trials; Analysis 8.6.2).
Modality of paracentesis
The test for subgroup differences comparing the effects of experimental plasma expanders versus albumin in participants treated by total compared to partial paracentesis showed no difference (P = 0.52, I² = 0%; Analysis 9.6).
Experimental plasma expanders did not affect hyponatraemia in comparison with albumin in the trials in which partial paracentesis was used (RR 1.00, 95% CI 0.29 to 3.51; 169 participants; 3 trials; I2 = 0%; Analysis 9.6.1). Experimental plasma expanders increased the risk of hyponatraemia in comparison with albumin in the trials in which total paracentesis was used (RR 1.54, 95% CI 1.05 to 2.26; 938 participants; 14 trials; I2 = 0%; Analysis 9.6.2).
Length of follow‐up
The test for subgroup differences comparing the effects of experimental plasma expanders versus albumin in people with a short (up to one month) follow‐up compared to a long follow‐up showed no difference (P = 0.56, I² = 0%; Analysis 10.7). Experimental plasma expanders versus albumin resulted in more participants with hyponatraemia in the trials with a short follow‐up (RR 1.64, 95% CI 1.01 to 2.68; 551 participants; 8 trials; I2 = 0%; Analysis 10.7.1). No difference was found in the trials with more than one month of follow‐up (RR 1.31, 95% CI 0.76 to 2.28; 556 participants; 9 trials; I2 = 0%; Analysis 10.7.2).
For‐profit support
The test for subgroup differences comparing funding support showed no difference between the two subgroups (P = 0.99, I2 = 0%; Analysis 11.6). We found no evidence of a difference in hyponatraemia either in the subgroup of trials without for‐profit funding (RR 1.48, 95% CI 0.79 to 2.77; 357 participants; 6 trials; I2 = 0%; Analysis 11.6.1) or in the subgroup of trials with or unknown for‐profit funding (RR 1.49, 95% CI 0.95 to 2.34; 750 participants; 11 trials; I2 = 0%; Analysis 11.6.2).
Post‐paracentesis circulatory dysfunction
Post‐paracentesis circulatory dysfunction was assessed in three trials including 432 participants (Ginès 1996; Sola‐Vera 2003; Al Sebaey 2012). Post‐paracentesis circulatory dysfunction was more frequent in participants treated by experimental plasma expanders in comparison with albumin (RR 1.98, 95% CI 1.31 to 2.99; P = 0.001; I2 = 0%; Analysis 7.8).
We assessed the level of certainty of the evidence for this outcome as very low. We downgraded the evidence by three levels because all trials were at high risk of bias; and imprecision: the required information size was not reached (Table 5; Table 6). Trial Sequential Analysis of this comparison was based on a post‐paracentesis circulatory dysfunction proportion of 14.8% in the albumin group, a relative risk reduction of 10% with experimental plasma expanders, a type I error of 2.00%, and a type II error of 20% (80% power). There was no diversity (D2 = 0%). The diversity‐adjusted required information size was 22,146 participants. The trial sequential monitoring boundary could not be constructed due to too little information (1.95%).
Subgroup analysis
We could not perform subgroup analysis of trials according to the risk of bias because all the trials were at high risk. In all three trials, the included participants were without refractory ascites and total paracentesis was used. So we could not perform subgroup analysis according to the presence of refractory ascites and to modality of paracentesis. Post‐paracentesis circulatory dysfunction by definition was assessed at six days after paracentesis. So we could not perform subgroup analysis according to length of follow‐up.
Type of plasma expanders
The test for subgroup differences comparing the effects of different plasma expanders showed no difference between the subgroups (P = 0.48; I² = 0%; Analysis 7.8). No evidence of a difference in post‐paracentesis circulatory dysfunction was reported in comparison with albumin in the trial assessing hydroxyethyl starch (RR 0.67, 95% CI 0.14 to 3.07; 75 participants; Analysis 7.8.2; Al Sebaey 2012). In comparison with albumin, there was an increased risk for post‐paracentesis circulatory dysfunction in the trials evaluating dextran (RR 1.99, 95% CI 1.04 to 3.81; 142 participants; Analysis 7.8.1; Ginès 1996), polygeline (RR 2.06, 95% CI 1.03 to 4.10; 147 participants; Analysis 7.8.3; Ginès 1996), and crystalloids (RR 2.92, 95% CI 1.03 to 8.26; 68 participants; Analysis 7.8.4; Sola‐Vera 2003).
For‐profit support
The test for subgroup differences comparing funding support showed no difference between the two subgroups (P = 0.73, I2 = 0%; Analysis 11.7). We found no evidence of a difference in post‐paracentesis circulatory dysfunction in the subgroup of trials without for‐profit funding (RR 1.56, 95% CI 0.37 to 6.51; 143 participants; 2 trials; I2 = 59%; Analysis 11.7.1). Experimental plasma expander versus albumin resulted in more participants with post‐paracentesis circulatory dysfunction in the single trial with for‐profit funding (RR 2.02, 95% CI 1.26 to 3.24; 289 participants; Analysis 11.7.2).
Reinfusion of ascitic fluid versus polygeline
One trial including 10 participants per comparison group assessed intravenous infusion of ascitic fluid versus polygeline (Mehta 1998). No procedure‐related mortality was reported in the trial, but all‐cause mortality was not reported. The trial did not report data on serious adverse events, health‐related quality of life, renal impairment, hypotension, hyponatraemia, and post‐paracentesis circulatory dysfunction. There was one liver‐related complication (spontaneous bacterial peritonitis) in the intravenous infusion of ascitic fluid group, and no events occurred in the polygeline group (P = 1.00) (Analysis 14.1). Non‐serious adverse events were more frequent in the intravenous infusion of ascitic fluid group than in the polygeline group (7 and 0, respectively, P = 0.003) (Analysis 14.2). Recurrence of ascites was similar in both treatment groups (9 and 10, respectively, P = 1.00) (Analysis 14.3).
Dextran versus polygeline
Ginès 1996 assessed dextran (93 participants) versus polygeline (99 participants). There were no differences between the two treatments in mortality (4/93 (4%) versus 6/99 (6%) (P = 0.74)); renal impairment (8/93 (9%) versus 10/99 (10%) (P = 0.80)); other liver‐related complications (12/93 (13%) versus 9/99 (9%) (P = 0.48)); non‐serious adverse events (0/93 versus 1/99 (1%) (P = 1.00)); hyponatraemia (23/93 (25%) versus 19/99 (19%) (P = 0.38)); and post‐paracentesis circulatory dysfunction (34/93 (36%) versus 34/99 (34%) (P = 0.76).
Comparison of imprecision with GRADE and with Trial Sequential Analysis
The optimal information size (OIS) obtained with GRADE based on the GRADE Handbook, and with GRADE based on authors' choice of plausible relative risk reduction (RRR), and the diversity‐adjusted required information size (DARIS) obtained by Trial Sequential Analysis (TSA) were not reached in any primary, secondary, and exploratory outcomes. The agreement in the evaluation of imprecision, obtained by the TSA and GRADE methods, was substantial. We reported the comparison of imprecision evaluation for the primary, secondary and exploratory outcomes in Table 1; Table 3; Table 4; Table 6.
Number needed to treat for a beneficial outcome
Number needed to treat for a beneficial outcome (NNTB) was not calculated for each outcome because we judged it was useless to attempt to give an absolute measure of the effect based on a very low level of certainty.
Data from the two trials not included in the meta‐analysis
In the García‐Compeán 2002 trial, the authors reported outcomes referring to the number of paracentesis procedures (48 in dextran group and 48 in albumin group) and not to the number of included participants for each group. There were no deaths during the first hospitalisation, and 18 and 11, respectively during the follow‐up in the two groups. Recurrence was observed in 34 and 30 participants in each group. There were no differences between Dextran 40 and albumin in the number and type of complications: renal impairment; hyponatraemia; hyperkalaemia; and local haematoma.
In the Degoricija 2003 trial, it was not possible to extract numerical data on the outcomes of interest for the meta‐analysis. The authors reported that the different plasma expanders (albumin, fresh frozen plasma, or polygeline) after a single paracentesis of 6 L, associated with 24‐h bed rest before and after the procedure, did not induce significant changes in clinical measurements and laboratory parameters of hepatic and renal function, and plasma renin activity. No local complications related to the procedures were observed.
We judged both the two trials to be at high risk of bias (Figure 2). No data on benefit or harm were available. Thus, it was not possible to assess the certainty of the evidence.
Adverse events reported in non‐randomised studies retrieved with the searches for this review
In the Zaak 2001 study, intravenous infusion of ascitic fluid was compared to albumin. Among the 14 participants treated by intravenous infusion of ascitic fluid, there were 11 deaths (78%), 8 complications (57%), 4 cases of hyponatraemia (28%), 1 case of renal impairment (7%), and 3 cases of hepatic encephalopathy (21%). Among the 21 participants treated with albumin, there were 16 deaths (76%), 3 cases of hyponatraemia (14%), 2 cases of renal impairment (9%), and 2 cases of hepatic encephalopathy (9%).
In the Nasr 2010 study, Dextran 70 was compared to albumin. None of the study participants developed serious complications in the form of spontaneous bacterial peritonitis, sepsis, bleeding, or increase in the grade of hepatic encephalopathy until discharge after one week at least.
Adverse events reported in other studies with insufficient information on design, conduct, and results, retrieved with the searches for this review
Antillon and colleagues referred to a randomised trial comparing albumin infusion versus no plasma expander after large volume paracentesis in people with cirrhosis and refractory ascites in three publications (Antillon 1990 ‐ abstract; Antillon 1991 ‐ letter of comment to the Planas 1990 trial; Antillon 1993 ‐ comment to the Bruno 1992 trial). In the abstract, they reported three deaths out of seven participants (43%) in the albumin group and two deaths out of seven participants (29%) in the no plasma expander group (Antillon 1990). In the letter of comment to Planas 1990, Antillon reported that, in their "ongoing trial" including 28 participants, the one‐year survival was 45.0% in the albumin group and 41.6% in the no plasma expander group, and that the incidence of hepatorenal syndrome was 50% and 33% in the two groups, respectively (Antillon 1991). However, they did not report the number of participants in each group. In the comment to the Bruno 1992 trial, they referred to the trial again as "ongoing" without new results (Antillon 1993). No further information, requested by email and letter, was obtained from the authors.
Analyses not planned in the protocol
Trials comparing different amounts of albumin
We assessed the effect of two different doses of albumin in a separate analysis: 4 g/L versus 8 g/L of removed ascites (Alessandria 2011) and 2 g/L versus 6 g/L of removed ascites (Al Sebaey 2013).
The trial by Alessandria 2011 assessed low versus high dose of albumin in 35 participants in each group. There were no differences in the doses administered to the two groups in terms of mortality (3 events in each group, P = 1.00); renal impairment (0 events in each group); other complications (4 and 5 events, respectively, P = 1.00); and hyponatraemia (3 and 2 respectively, P = 1.00).
Post‐paracentesis circulatory dysfunction, assessed in the Al Sebaey 2013 and Alessandria 2011 trials, was similar between the two groups: 8/60 events in the low dose albumin group and 10/60 in high dose albumin group (RR 1.00, 95% CI 0.22 to 4.49; 120 participants; I2 = 0) (forest‐plot not shown).
Trials including participants with acute‐on‐chronic liver failure
One randomised clinical trial, published as abstracts (Arora 2018a; Arora 2018b), compared albumin with no plasma expander after a single < 5 L paracentesis in participants with acute‐on‐chronic liver failure (ACLF).
Forty participants received albumin (8 g/L of ascitic fluid) and forty received no plasma expander.
Albumin versus no plasma expansion reduced acute kidney injury (12/40 versus 25/40, P = 0.0067), hyponatraemia (9/40 versus 27/40, P = 0.0001), post‐paracentesis circulatory dysfunction (12/40 versus 28/40, P = 0.0007), but not hepatic encephalopathy (11/40 versus 20/40, P = 0.07). People without post‐paracentesis circulatory dysfunction (PPCD) had a higher mortality than people with PPCD (10/40 compared to 26/40, P = 0.0006).
Acute‐on‐chronic liver failure has peculiar pathophysiological, clinical, and prognostic features (Arroyo 2016).
Discusión
Resumen de los resultados principales
Esta revisión sistemática con metanálisis evaluó el papel de los expansores del plasma tras una paracentesis terapéutica para la ascitis de gran volumen en personas con cirrosis. La revisión trató de responder a dos preguntas: si los expansores del plasma son necesarios y si existe alguna diferencia entre expansores del plasma.
Cinco ensayos con 271 participantes compararon expansores del plasma versus ningún expansor. La albúmina se utilizó en cuatro estudios (Ginès 1988; García‐Compeán 1993; Luca 1995; Baik 2000). La infusión intravenosa de líquido ascítico concentrado o no modificado se utilizó en un ensayo (Descos 1983). La mayoría de los ensayos estaban diseñados solo para evaluar resultados durante la hospitalización. Dos ensayos evaluaron las alteraciones hemodinámicas inmediatas (al día o dos días) tras la paracentesis (Luca 1995; Baik 2000). Sólo un ensayo informó el seguimiento tras el alta (Ginès 1988).
Se encontró evidencia de certeza muy baja de que los expansores del plasma podrían lograr poco o ningún cambio en la mortalidad. Se encontró evidencia de certeza muy baja de que los expansores del plasma podrían lograr poco o ningún cambio en la mortalidad los eventos adversos, la insuficiencia renal, otras complicaciones relacionadas con el hígado, eventos adversos no graves, recurrencia de ascitis e hiponatremia. Se halló evidencia de certeza muy baja de que la albúmina reduce el riesgo de hiponatremia en el subgrupo de ensayos en los que se utilizó paracentesis parcial, con un seguimiento de más de un mes y sin financiación lucrativa. No se detectó evidencia de una diferencia para cada uno de los otros resultados en los análisis de subgrupos con respecto al tipo de expansor del plasma, la modalidad de paracentesis ni la duración del seguimiento. Ningún ensayo evaluó la calidad de vida relacionada con la salud, la incidencia de ascitis refractaria ni la disfunción circulatoria posparacentesis.
Veintiún estudios, que incluyeron a 1291 participantes, evaluaron los diferentes expansores del plasma versus albúmina (Planas 1990; Smart 1990; Bertrán 1991; Salerno 1991; Simonetti 1991; Bruno 1992; Fassio 1992; Méndez 1991; Hernández Pérez 1995; Ginès 1996; Graziotto 1997; Altman 1998; Kang 1998; Zhao 2000; García‐Compeán 2002; Sola‐Vera 2003; Moreau 2006; Abdel‐Khalek 2010; Al Sebaey 2012; Khan 2015) o versus otro expansor del plasma (Mehta 1998).
Se encontró evidencia de certeza muy baja de que los expansores del plasma experimentales podrían lograr poco o ningún cambio en la mortalidad. No se halló evidencia de una diferencia en la mortalidad al analizar cada expansor del plasma experimental (dextrano, poligelina, hidroxietilalmidón, infusión intravenosa de líquido ascítico, manitol, solución salina) versus albúmina. No se encontró evidencia de una diferencia en la mortalidad en los subgrupos de ensayos que incluyeron participantes con ascitis refractaria o sin ascitis refractaria, tratados con diferentes modalidades de paracentesis (paracentesis total en una sesión o parcial‐repetida), con distintas duraciones de seguimiento (hasta un mes o más de un mes) y tipo de financiación. Ningún ensayo evaluó la calidad de vida relacionada con la salud ni la incidencia de ascitis refractaria. Se encontró evidencia de certeza muy baja de que los expansores del plasma experimentales versus albúmina podrían lograr poco o ningún cambio en la mortalidad los eventos adversos, la insuficiencia renal, otras complicaciones relacionadas con el hígado, eventos adversos no graves y recurrencia de ascitis.
Se encontró evidencia de certeza muy baja de que los expansores del plasma experimentales versus albúmina aumentaron la incidencia de hiponatremia.
La hiponatremia se asocia con un riesgo significativamente mayor de muerte en cirrosis (Ginés 2008; Mohanty 2015). Kim y colegas mostraron que el sodio sérico en pacientes en lista de espera para un trasplante hepático es un predictor importante de mortalidad, independientemente de la puntuación del modelo para la enfermedad hepática terminal ( model for end‐stage liver disease [MELD]) (Kim 2008). Si esta asociación es atribuible a la propia hiponatremia o refleja el hecho de que los pacientes con hiponatremia tienden a estar enfermos en general, está por determinar. El MELD‐Na, que incluye sodio sérico, ha mostrado predecir la supervivencia de forma más exacta que el MELD solo (Biggins 2006) y se propuso como puntuación pronóstica para identificar pacientes para su inclusión en la lista de espera de trasplante hepático. Además, la hiponatremia está relacionada con un mayor riesgo de encefalopatía hepática (Guevara 2009; Guevara 2010) y a una calidad de vida relacionada con la salud deficiente (Sola 2012). En esta revisión sistemática, hubo un mayor riesgo de hiponatremia, pero no de mortalidad, con expansores del plasma experimentales distintos de la albúmina, por lo que no está claro el significado pronóstico del mayor riesgo de hiponatremia.
Tres ensayos proporcionaron evidencia de certeza muy baja de que los expansores del plasma experimentales versus albúmina aumentaron la incidencia de disfunción circulatoria posparacentesis, abordada según la definición formal propuesta por Ginès 1996 y colegas (Ginès 1996; Sola‐Vera 2003; Al Sebaey 2012). La disfunción circulatoria posparacentesis se define como un aumento de la actividad de renina plasmática de más del 50% del valor anterior al tratamiento a un nivel de más de 4 ng/ml/h en el sexto día posterior a la paracentesis (Ginès 1996, Ruiz‐del‐Arbol 1997). El aumento en la actividad de la renina sugiere una activación del mecanismo neurohumoral para mantener la homeostasis correcta cuando se induce la reducción del volumen plasmático efectivo por paracentesis (Ruiz‐del‐Arbol 1997), lo cual interfiere con el equilibrio precario y extremadamente sensible del mecanismo homeostático en pacientes con cirróticos ascítica. Sin embargo, la relación de la disfunción circulatoria posparacentesis con el pronóstico no está documentada de forma definitiva, ya que es un resultado indirecto no validado de los efectos clínicos (Gluud 2007; Jakobsen 2017; Jakobsen 2018). Además, en muchos ensayos, puesto que la actividad de la renina se analiza en diferentes puntos temporales y mediante distintos valores de corte, la relación con el pronóstico es totalmente inexistente.
En el análisis de subgrupos se encontró evidencia de certeza muy baja de que los expansores del plasma experimentales versus la albúmina aumentaron la incidencia de otras complicaciones relacionadas con el hígado en los ensayos que incluyeron a personas sin ascitis refractaria y en los ensayos sin financiación lucrativa, la recurrencia de la ascitis en los ensayos con un seguimiento corto, la hiponatremia en los ensayos que incluyeron a personas sin ascitis refractaria, en ensayos en los que se usó la paracentesis total y en ensayos con un seguimiento corto. Respecto al tipo de expansores del plasma, se halló evidencia de certeza muy baja de que el hidroxietilalmidón aumentó el riesgo de recurrencia; la poliglina, el dextrano y los cristaloides aumentaron el riesgo de disfunción circulatoria posparacentesis; y la infusión intravenosa de líquido ascítico redujo el riesgo de otras complicaciones relacionadas con el hígado. Los expansores del plasma experimentales aumentaron el riesgo de disfunción circulatoria posparacentesis en ensayos con financiación lucrativa. No se hallaron diferencias en los subgrupos restantes.
En general, los datos para la realización de análisis de subgrupos fueron escasos.
Las diferencias entre los expansores del plasma experimentales versus la albúmina en algunos resultados secundarios y exploratorios y en algunos análisis de subgrupos no pueden considerarse prueba de ningún efecto de la intervención, teniendo en cuenta la evidencia de certeza muy baja, el significado clínico incierto de los resultados exploratorios y el número de comparaciones que podría generar resultados de falso positivo. No obstante, tales diferencias podrían actuar como estímulo para realizar más ensayos clínicos aleatorizados.
Compleción y aplicabilidad general de las pruebas
Los participantes del ensayo incluido tenían una amplia gama de características, pero su estadio de cirrosis no estaba muy avanzado, ya que los criterios de exclusión en algunos de los ensayos fueron la presencia de carcinoma hepatocelular, hemorragia gastrointestinal reciente, encefalopatía hepática e infección reciente. En la mayoría de estos ensayos, los participantes no tenían insuficiencia renal ni hiponatremia. Algunos ensayos no describieron claramente si los participantes del ensayo tenían ascitis refractaria. Así pues, con base en el resumen de la evidencia, se concluye que los resultados solo son aplicables a personas con cirrosis en estadio intermedio a avanzado, habitualmente tratados con paracentesis en los centros.
Esta revisión sistemática con metanálisis indica que no existe suficiente evidencia sobre si los expansores del plasma son mejores que la ausencia de expansores del plasma. Esta comparación debe mostrar que los expansores del plasma son superiores a la ausencia de estos antes de interesarse por comparar los diferentes expansores del plasma entre sí. Sin tal información, es difícil interpretar la comparación entre los expansores del plasma experimentales versus albúmina o versus otros expansores del plasma.
Calidad de la evidencia
La revisión actual ha identificado varias preocupaciones metodológicas. Todos los ensayos presentaron un alto riesgo de sesgo. Además, hubo riesgos altos de errores aleatorios. No se alcanzó el número de participantes requerido a priori para un metanálisis concluyente, por lo que este metanálisis no tiene suficiente información para rechazar o aceptar las hipótesis.
Las evaluaciones del riesgo de sesgo y, por lo tanto, la certeza de la evidencia, reflejan una falta de descripción o una mala descripción del diseño y la realización de los ensayos, así como un informe incompleto de los resultados. A menudo no se consiguió obtener la información faltante por parte de los autores de los informes de los ensayos. Además, existe un riesgo de efectos fortuitos debido a la realización de varios análisis.
Se utilizó GRADE para considerar el efecto de las limitaciones de los estudios en los resultados. La conclusión es que la certeza de la información es muy baja. Cuando se evaluó en un análisis de sensibilidad la imprecisión con el Trial Sequential Analysis, la evaluación de la certeza de la evidencia también fue muy baja; observaciones de acuerdo con estudios previos (Castellini 2018; Gartlehner 2018).
Sesgos potenciales en el proceso de revisión
Se realizó una búsqueda exhaustiva de la literatura para identificar estudios publicados y no publicados. Además, se combinaron las búsquedas en bases de datos electrónicas con búsquedas manuales de las listas de referencias de los estudios identificados y también de las actas de congresos y libros de resúmenes de congresos relevantes de sociedades nacionales e internacionales. Se incluyeron ensayos sin importar su idioma de publicación y si informaron datos sobre los resultados necesarios. Se estableció contacto con los autores relevantes para obtener información adicional.
Se consideró improbable el fracaso en la identificación de algún ensayo publicado o no publicado. Dos autores de la revisión evaluaron de forma independiente la elegibilidad de los estudios, extrajeron los datos y evaluaron el riesgo de sesgo en los estudios incluidos, y se cree que este hecho redujo el sesgo potencial en el proceso de revisión. Se incluyeron solo ensayos cuasialeatorizados y no estudios observacionales para evaluar los eventos adversos. Esto podría haber sesgado la revisión hacia la evaluación de los beneficios y podría haber pasado por alto efectos perjudiciales tardíos o poco frecuentes. No se buscó la traducción del informe de estudio completo para dos estudios informados en coreano (Kang 1998; Baik 2000); los juicios de los autores de la revisión y los datos estuvieron limitados por la información disponible en el resumen y en las tablas.
Acuerdos y desacuerdos con otros estudios o revisiones
Se han publicado varios metanálisis sobre el uso de la albúmina y otros expansores del plasma en pacientes cirróticos con ascitis que recibieron paracentesis (Wong 2008; Bernardi 2012; Wang 2015; Kütting 2017).
El metanálisis de Wong 2008 con nueve ensayos no halló diferencias en la morbimortalidad (insuficiencia renal, encefalopatía hepática, hiponatremia) entre la expansión plasmática versus ninguna expansión plasmática y entre otros expansores del plasma versus albúmina. El metanálisis de Bernardi 2012, con 17 ensayos halló que la albúmina en comparación con otros expansores del plasma y vasoconstrictores como terlipresina, norepinefrina y midodrina, redujo la mortalidad, la hiponatremia y la disfunción circulatoria posparacentesis y que la albúmina en la comparación con ningún tratamiento redujo la hiponatremia y la disfunción circulatoria posparacentesis. No obstante, Chen 2014 y colegas publicaron una carta en la que presentaban el Trial Sequential Analysis de los datos de metanálisis de Bernardi que no confirmaba sus resultados y conclusiones. Por otro lado, la respuesta de Bernardi confirmó las conclusiones del metanálisis de Bernardi 2012 (Bernardi 2014). El metanálisis de Wang 2015 con 13 ensayos halló que la infusión de albúmina tuvo una ventaja sobre los tratamientos alternativos en la reducción de la mortalidad hospitalaria, la hiponatremia y la disfunción circulatoria posparacentesis. Por su parte, Kütting y colegas (Kütting 2017), en su metanálisis de 21 ensayos que evaluó la albúmina versus ningún expansor del plasma, otros expansores del plasma y vasoconstrictores, no halló suficiente evidencia del beneficio en la mortalidad debido a la sustitución con albúmina en pacientes cirróticos sin carcinoma hepatocelular sometidos a paracentesis de volumen grande.
Las conclusiones discrepantes en los anteriores metanálisis y en la presente revisión pueden explicarse por las diferencias en la metodología de revisión sistemática, tratamientos analizados y la selección de las medidas de resultado. Esta revisión es la única basada en un protocolo prepublicado actualizado conforme a la metodología Cochrane actualizada durante el tiempo de preparación de la revisión. Se utilizó el Trial Sequential Analysis para controlar los riesgos de errores aleatorios a los cuales se expone el metanálisis convencional (Wetterslev 2008; Thorlund 2010; Jakobsen 2014; Gluud 2015).
La búsqueda de ensayos clínicos aleatorizados está actualizada hasta enero de 2019, lo que resultó en la inclusión de más ensayos de los que incluyeron los metanálisis anteriores.
Se abordaron, en dos comparaciones separadas, el papel de un expansor del plasma versus ningún expansor del plasma y el papel de distintos expansores del plasma, de forma similar a Wong (Wong 2008) y Bernardi (Bernardi 2012). Kutting y colegas analizaron juntos los ensayos en los que los expansores del plasma se estudiaban frente a ningún tratamiento y frente a otros expansores del plasma (Kütting 2017). Wang no incluyó ensayos que compararan expansores del plasma versus ningún tratamiento (Wang 2015).
En esta revisión sistemática, para tener una mayor homogeneidad de los tratamientos evaluados, se escogió evaluar solo sustancias cuyo objetivo fuera mantener un equilibrio correcto tras la paracentesis mediante el aumento del volumen intravascular (líquidos o coloides). Se excluyeron tratamientos que actuaran aumentando la resistencia periférica, como los vasoconstrictores terlipresina, norepinefrina y midodrina, incluidos en los metanálisis de Bernardi, Wang y Kutting (Bernardi 2012, Wang 2015; Kütting 2017).
Se incluyeron todos los ensayos que evaluaron cada infusión intravenosa de líquidos que puedan actuar como expansores del plasma y analizados en relación con la paracentesis, incluida la infusión intravenosa de líquido ascítico tras la filtración y, en algunos casos, la concentración, excluidos en otros metanálisis. La justificación de su uso no difiere de la de otros expansores del plasma, como coloides o solución salina.
Tras la publicación del ensayo de Ginès 1988, se consideró que la albúmina fue beneficiosa, pero cara, en relación con la paracentesis. Muchos ensayos se realizaron evaluando expansores del plasma más baratos o un sistema modificado de infusión intravenosa de líquido ascítico versus albúmina. En esta revisión sistemática se decidió analizar “expansores del plasma que no fueran albúmina” como tratamiento experimental versus albúmina como tratamiento de control, para acercarse más a la estructura real de los ensayos realizados, mientras que en los otros metanálisis, la albúmina se analizó como tratamiento experimental.
Una diferencia importante entre esta revisión y los metanálisis realizados por otros fue la elección de los resultados, clasificados como primarios, secundarios y exploratorios según su importancia clínica. En concreto, la hiponatremia y la disfunción circulatoria posparacentesis se escogieron como resultados exploratorios en la actual revisión, mientras que en Bernardi 2012 fueron resultados primarios junto con la mortalidad y en Kütting 2017 fueron resultados secundarios. Nuestra elección se debe al supuesto carácter indirecto de la hiponatremia y la disfunción circulatoria posparacentesis (ver más arriba).
Además, con respecto a la disfunción circulatoria posparacentesis, se siguió la definición de Ginès (Ginès 1996), que es a la cual se refiere habitualmente la comunidad científica. Se incluyó el ensayo Al Sebaey 2012 porque la definición de disfunción circulatoria posparacentesis fue solo ligeramente diferente de la de Ginès 1996. Por el contrario, Bernardi 2012 y Kütting 2017 definieron la disfunción circulatoria posparacentesis en el apartado de métodología como un aumento de la actividad de la renina plasmática ≥ 50% (independientemente del tiempo de observación), pero después en el apartado de resultados informaron bajo el nombre de disfunción circulatoria pos cualquier alteración en la actividad de la renina, independientemente de la tasa de aumento y el momento de la evaluación, así como cualquier cambio en los niveles de aldosterona. La relación de estos cambios humorales y las diferencias entre los tratamientos con resultados clínicos y pronósticos robustos no han sido analizadas ni validadas.
En un ensayo reciente (Caraceni 2018), la administración de albúmina a largo plazo en participantes con cirrosis y ascitis no complicada tratados con diuréticos aumentó la supervivencia y redujo la incidencia de complicaciones. Este ensayo no evaluó el papel de la albúmina tras la paracentesis terapéutica. La albúmina se administró en un régimen semanal fijo asociado con el tratamiento médico estándar durante hasta 18 meses. Además, la mayoría de participantes tenían ascitis moderada (grado 2), sin ascitis refractaria. Por el contrario, los ensayos de la actual revisión sistemática evaluaron los efectos beneficiosos y perjudiciales de cualquier expansor del volumen plasmático versus ningún expansor del volumen plasmático o versus otro expansor del volumen plasmático tras la paracentesis, incluyeron principalmente a participantes con ascitis de gran volumen y algunos ensayos incluyeron participantes con ascitis refractaria. Por lo tanto, el ensayo de Caraceni no encajó con la pregunta de la revisión sistemática y sus resultados no pueden aplicarse a pacientes tratados con paracentesis. No obstante, pueden hacer surgir temas estimulantes sobre el papel de la albúmina como tratamiento modificador de la enfermedad prometedor (Bernardi 2018).
.
Study flow diagram.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Funnel plot of comparison: 6 Experimental plasma expanders versus albumin, outcome: 6.1 All‐cause mortality.
Experimental plasma expanders versus albumin ‐ 6.1 All‐cause mortality.
The diversity‐adjusted required information size of 16,415 participants was calculated based on a proportion of participants of 18.2% of participants dying in the control group; a relative risk reduction (RRR) of 10% in the plasma expander group; an alpha of 2.5%; a power of 80%; and a diversity of 0%.
The cumulative Z score did not cross borders for benefit, harm, or futility.
Funnel plot of comparison: 6 Experimental plasma expanders versus albumin, outcome: 6.3 Renal impairment.
Funnel plot of comparison: 6 Experimental plasma expanders versus albumin, outcome: 6.4 Other liver‐related complications.
Experimental plasma expander versus albumin ‐ 6.4 Other liver‐related complications.
The diversity‐adjusted required information size of 16,992 participants was calculated based on a proportion of participants of 18.5% with other liver‐related complications in the control group; a relative risk reduction (RRR) of 10% in the plasma expander group; an alpha of 2.00%; a power of 80%; and a diversity of 0%.
The cumulative Z score did not cross borders for benefit, harm, or futility.
Funnel plot of comparison: 6 Experimental plasma expanders versus albumin, outcome: 6.5 Non‐serious adverse events.
Funnel plot of comparison: 6 Experimental plasma expanders versus albumin, outcome: 6.6 Recurrence of ascites.
Experimental plasma expanders versus albumin ‐ 6.6 Recurrence of ascites.
The diversity‐adjusted required information size of 7104 participants was calculated based on a proportion of participants of 36.3% of participants suffering recurrence of ascites in the control group; a relative risk reduction (RRR) of 10% in the plasma expander group; an alpha of 2%; a power of 80%; and a diversity of 3%.
The cumulative Z score did not cross borders for benefit, harm, or futility.
Funnel plot of comparison: 6 Experimental plasma expanders versus albumin, outcome: 6.7 Hyponatraemia.
Comparison 1 Plasma expanders versus no plasma expander, Outcome 1 All‐cause mortality.
Comparison 1 Plasma expanders versus no plasma expander, Outcome 2 Serious adverse events.
Comparison 1 Plasma expanders versus no plasma expander, Outcome 3 Renal impairment.
Comparison 1 Plasma expanders versus no plasma expander, Outcome 4 Other liver‐related complications.
Comparison 1 Plasma expanders versus no plasma expander, Outcome 5 Non‐serious adverse events.
Comparison 1 Plasma expanders versus no plasma expander, Outcome 6 Recurrence of ascites.
Comparison 1 Plasma expanders versus no plasma expander, Outcome 7 Hyponatraemia.
Comparison 2 Subgroup analysis of plasma expanders versus no plasma expander regarding modality of paracentesis, Outcome 1 All‐cause mortality.
Comparison 2 Subgroup analysis of plasma expanders versus no plasma expander regarding modality of paracentesis, Outcome 2 Renal impairment.
Comparison 2 Subgroup analysis of plasma expanders versus no plasma expander regarding modality of paracentesis, Outcome 3 Other liver‐related complications.
Comparison 2 Subgroup analysis of plasma expanders versus no plasma expander regarding modality of paracentesis, Outcome 4 Non‐serious adverse events.
Comparison 2 Subgroup analysis of plasma expanders versus no plasma expander regarding modality of paracentesis, Outcome 5 Hyponatraemia.
Comparison 3 Subgroup analysis of plasma expanders versus no plasma expander regarding duration of follow‐up, Outcome 1 All‐cause mortality.
Comparison 3 Subgroup analysis of plasma expanders versus no plasma expander regarding duration of follow‐up, Outcome 2 Renal impairment.
Comparison 3 Subgroup analysis of plasma expanders versus no plasma expander regarding duration of follow‐up, Outcome 3 Other liver‐related complications.
Comparison 3 Subgroup analysis of plasma expanders versus no plasma expander regarding duration of follow‐up, Outcome 4 Non‐serious adverse events.
Comparison 3 Subgroup analysis of plasma expanders versus no plasma expander regarding duration of follow‐up, Outcome 5 Hyponatraemia.
Comparison 4 Subgroup analysis of plasma expanders versus no plasma expander regarding funding, Outcome 1 All‐cause mortality.
Comparison 4 Subgroup analysis of plasma expanders versus no plasma expander regarding funding, Outcome 2 Renal impairment.
Comparison 4 Subgroup analysis of plasma expanders versus no plasma expander regarding funding, Outcome 3 Other liver‐related complications.
Comparison 4 Subgroup analysis of plasma expanders versus no plasma expander regarding funding, Outcome 4 Non‐serious adverse events.
Comparison 4 Subgroup analysis of plasma expanders versus no plasma expander regarding funding, Outcome 5 Hyponatraemia.
Comparison 5 Plasma expanders versus no plasma expander: best‐worst case scenario analysis, Outcome 1 All‐cause mortality.
Comparison 6 Plasma expanders versus no plasma expander: worst‐best case scenario analysis, Outcome 1 All‐cause mortality.
Comparison 7 Experimental plasma expanders versus albumin, Outcome 1 All‐cause mortality.
Comparison 7 Experimental plasma expanders versus albumin, Outcome 2 Serious adverse events.
Comparison 7 Experimental plasma expanders versus albumin, Outcome 3 Renal impairment.
Comparison 7 Experimental plasma expanders versus albumin, Outcome 4 Other liver‐related complications.
Comparison 7 Experimental plasma expanders versus albumin, Outcome 5 Non‐serious adverse events.
Comparison 7 Experimental plasma expanders versus albumin, Outcome 6 Recurrence of ascites.
Comparison 7 Experimental plasma expanders versus albumin, Outcome 7 Hyponatraemia.
Comparison 7 Experimental plasma expanders versus albumin, Outcome 8 Post‐paracentesis circulatory dysfunction.
Comparison 8 Subgroup analysis of experimental plasma expanders versus albumin regarding presence or absence of refractory ascites, Outcome 1 All‐cause mortality.
Comparison 8 Subgroup analysis of experimental plasma expanders versus albumin regarding presence or absence of refractory ascites, Outcome 2 Renal impairment.
Comparison 8 Subgroup analysis of experimental plasma expanders versus albumin regarding presence or absence of refractory ascites, Outcome 3 Other liver‐related complications.
Comparison 8 Subgroup analysis of experimental plasma expanders versus albumin regarding presence or absence of refractory ascites, Outcome 4 Non‐serious adverse events.
Comparison 8 Subgroup analysis of experimental plasma expanders versus albumin regarding presence or absence of refractory ascites, Outcome 5 Recurrence of ascites.
Comparison 8 Subgroup analysis of experimental plasma expanders versus albumin regarding presence or absence of refractory ascites, Outcome 6 Hyponatraemia.
Comparison 9 Subgroup analysis of experimental plasma expanders versus albumin regarding modality of paracentesis, Outcome 1 All‐cause mortality.
Comparison 9 Subgroup analysis of experimental plasma expanders versus albumin regarding modality of paracentesis, Outcome 2 Renal impairment.
Comparison 9 Subgroup analysis of experimental plasma expanders versus albumin regarding modality of paracentesis, Outcome 3 Other liver‐related complications.
Comparison 9 Subgroup analysis of experimental plasma expanders versus albumin regarding modality of paracentesis, Outcome 4 Non‐serious adverse events.
Comparison 9 Subgroup analysis of experimental plasma expanders versus albumin regarding modality of paracentesis, Outcome 5 Recurrences of ascites.
Comparison 9 Subgroup analysis of experimental plasma expanders versus albumin regarding modality of paracentesis, Outcome 6 Hyponatraemia.
Comparison 10 Subgroup analysis of experimental plasma expanders versus albumin regarding duration of follow‐up, Outcome 1 All‐cause mortality.
Comparison 10 Subgroup analysis of experimental plasma expanders versus albumin regarding duration of follow‐up, Outcome 2 Serious adverse events.
Comparison 10 Subgroup analysis of experimental plasma expanders versus albumin regarding duration of follow‐up, Outcome 3 Renal impairment.
Comparison 10 Subgroup analysis of experimental plasma expanders versus albumin regarding duration of follow‐up, Outcome 4 Other liver‐related complications.
Comparison 10 Subgroup analysis of experimental plasma expanders versus albumin regarding duration of follow‐up, Outcome 5 Non‐serious adverse events.
Comparison 10 Subgroup analysis of experimental plasma expanders versus albumin regarding duration of follow‐up, Outcome 6 Recurrence of ascites.
Comparison 10 Subgroup analysis of experimental plasma expanders versus albumin regarding duration of follow‐up, Outcome 7 Hyponatraemia.
Comparison 11 Subgroup analysis of experimental plasma expanders versus albumin regarding funding, Outcome 1 All‐cause mortality.
Comparison 11 Subgroup analysis of experimental plasma expanders versus albumin regarding funding, Outcome 2 Renal impairment.
Comparison 11 Subgroup analysis of experimental plasma expanders versus albumin regarding funding, Outcome 3 Other liver‐related complications.
Comparison 11 Subgroup analysis of experimental plasma expanders versus albumin regarding funding, Outcome 4 Non‐serious adverse events.
Comparison 11 Subgroup analysis of experimental plasma expanders versus albumin regarding funding, Outcome 5 Recurrence of ascites.
Comparison 11 Subgroup analysis of experimental plasma expanders versus albumin regarding funding, Outcome 6 Hyponatraemia.
Comparison 11 Subgroup analysis of experimental plasma expanders versus albumin regarding funding, Outcome 7 Post‐paracentesis circulatory dysfunction.
Comparison 12 Experimental plasma expanders versus albumin ‐ best‐worst case scenario, Outcome 1 All‐cause mortality.
Comparison 13 Experimental plasma expanders versus albumin ‐ worst‐best case scenario, Outcome 1 All‐cause mortality.
Comparison 14 Intravenous infusion of ascites versus polygeline, Outcome 1 Other liver‐related complications.
Comparison 14 Intravenous infusion of ascites versus polygeline, Outcome 2 Non‐serious adverse events.
Comparison 14 Intravenous infusion of ascites versus polygeline, Outcome 3 Recurrence of ascites.
| Plasma expanders versus no plasma expanders for people with cirrhosis and large ascites treated with abdominal paracentesis: primary and secondary outcomes | ||||||
| Patient or population: cirrhotic participants with large ascites treated by paracentesis Settings: specialised units in an intensive or semi‐intensive setting Intervention: plasma expander Comparison: no plasma expander | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No plasma expander | Plasma expander | |||||
| All‐cause mortality mean follow‐up 64 days (1‐222) | Medium risk population | RR 0.52 (0.06 to 4.83) | 248 | ⊕⊝⊝⊝ | ||
| 180 per 1000 | 94 per 1000 | |||||
| Serious adverse events mean follow‐up 15 days (1‐30) | See comment | See comment | See comment | 108 | ⊕⊝⊝⊝ | Two trials reported that no serious adverse events occurred |
| Health‐related quality of life | No data provided in any of the six trials | |||||
| Refractory ascites | No data provided in any of the six trials | |||||
| Other liver‐related complications mean follow‐up 64 days (1‐222) | Medium risk population | RR 1.61 (0.79 to 3.27) | 248 | ⊕⊝⊝⊝ | ||
| 90 per 1000 | 145 per 1000 | |||||
| Non‐serious adverse events mean follow‐up 91 days (1‐222) | Medium risk population | RR 1.04 (0.32 to 3.4) | 158 | ⊕⊝⊝⊝ | ||
| 62 per 1000 | 64 per 1000 | |||||
| * Assumed risk is the risk in comparison group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded 4 levels because of within study risk of bias: all trials were at high risk of bias (‐2 levels); heterogeneity: high heterogeneity (76%) (‐1 level); imprecision: the required information size as calculated by GRADE was not reached (‐1 level) | ||||||
| Other plasma expanders versus albumin for people with cirrhosis and large ascites treated with abdominal paracentesis: primary and secondary outcomes | ||||||
| Patient or population: cirrhotic participants with large ascites treated by paracentesis Settings: specialised units in an intensive or semi‐intensive setting Intervention: all plasma expanders except albumin Comparison: albumin | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Certainty of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Albumin | Experimental plasma expanders | |||||
| All‐cause mortality mean follow‐up 208 days (3‐638) | Medium risk population | RR 1.03 (0.82 to 1.30) | 1014 | ⊕⊝⊝⊝ very low 1 | ||
| 183 per 1000 | 188 per 1000 | |||||
| Serious adverse events mean follow‐up 93 days (6‐180) | Medium risk population | RR 0.89 (0.10 to 8.30) | 118 | ⊕⊝⊝⊝ very low 2 | ||
| 18 per 1000 | 16 per 1000 | |||||
| Health‐related quality of life | No data provided in any of the 20 trials | |||||
| Refractory ascites | No data provided in any of the 20 trials | |||||
| Renal impairment mean follow‐up 174 days (3‐628) | Medium risk population | RR 1.17 (0.71 to 1.91) | 1107 | ⊕⊝⊝⊝ | ||
| 49 per 1000 | 57 per 1000 | |||||
| Other liver‐related complications mean follow‐up 147 days (3‐638) | Medium risk population | RR 1.10 (0.82 to 1.48) | 1083 | ⊕⊝⊝⊝ | ||
| 185 per 1000 | 203 per 1000 | |||||
| Non‐serious adverse events mean follow‐up 194 days (3‐638) | Medium risk population | RR 1.37 (0.66 to 2.85) | 977 (14) | ⊕⊝⊝⊝ | ||
| 25 per 1000 | 34 per 1000 | |||||
| * Assumed risk is the risk in comparison group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded 4 levels because of within study risk of bias: all trials were at high risk of bias (‐2 levels); imprecision: the required information size as calculated by GRADE was not reached (‐1 level); publication bias (‐1 level) | ||||||
| Comparison of imprecision evaluation with GRADE based on the GRADE Handbook, with GRADE based on authors' choice of plausible relative risk reduction and multiplicity correction, and according to our Trial Sequential Analysis with a similar choice of plausible relative risk reduction and multiplicity correction, in addition to considering the choice of meta‐analytic model and diversity | |||||||
| Outcome | Proportion in control group | Relative risk reduction | Alpha | Beta | Diversity | Required information size (OIS or DARIS) | Downgrading of evidence for imprecision based on required information size |
| All‐cause mortality ‐‐ GRADE Handbook | 18% | 25% | 5% | 20% | Not used | 2056 | One level |
| All‐cause mortality ‐‐ GRADE plausible RRR | 18% | 10% | 2.5% | 20% | Not used | 16,634 | One level |
| All‐cause mortality ‐‐ TSA | 18% | 10% | 2.5% | 20% | 88% | 143,664 | One level |
| Serious adverse events ‐‐ GRADE Handbook (1) | |||||||
| Serious adverse events ‐‐ GRADE plausible RRR (1) | |||||||
| Serious adverse events ‐‐ TSA (1) | |||||||
| Health‐related quality of life ‐‐ GRADE Handbook | No data | ||||||
| Health‐related quality of life ‐‐ GRADE plausible RRR | No data | ||||||
| Health‐related quality of life ‐‐ TSA | No data | ||||||
| Refractory ascites ‐‐ GRADE Handbook | No data | ||||||
| Refractory ascites ‐‐ GRADE plausible RRR | No data | ||||||
| Refractory ascites ‐‐ TSA | No data | ||||||
| Renal impairment ‐‐ GRADE Handbook | 9.8% | 25% | 5% | 20% | Not used | 4100 | One level |
| Renal impairment ‐‐ GRADE plausible RRR | 9.8% | 10% | 2.00% | 20% | Not used | 35,290 | One level |
| Renal impairment ‐‐ TSA | 9.8% | 10% | 2.00% | 20% | 0% | 35,293 | One level |
| Other liver‐related complications ‐‐ GRADE Handbook | 9% | 25% | 5% | 20% | Not used | 4498 | One level |
| Other liver‐related complications ‐‐ GRADE plausible RRR | 9% | 10% | 2.00% | 20% | Not used | 38,750 | One level |
| Other liver‐related complications ‐‐ TSA | 9% | 10% | 2.00% | 20% | 0% | 38,752 | One level |
| Non‐serious adverse events ‐‐ GRADE Handbook | 6.25% | 25% | 5% | 20% | Not used | 6670 | One level |
| Non‐serious adverse events ‐‐ GRADE plausible RRR | 6.25% | 10% | 2.00% | 20% | Not used | 56,464 | One level |
| Non‐serious adverse events ‐‐ TSA | 6.25% | 10% | 2.00% | 20% | 0% | 56,467 | One level |
| (1) Serious adverse events: 0/68 in plasma expander group and 0/40 in no plasma expander group, RR 1.00 (95% CI 0.00 to 217…) OIS: optimal information size; DARIS: diversity‐adjusted required information size; RRR: relative risk reduction; TSA: Trial Sequential Analysis | |||||||
| Plasma expanders versus no plasma expander for people with cirrhosis and large ascites treated with abdominal paracentesis: exploratory outcomes | ||||||
| Patient or population: cirrhotic participants with large ascites treated by paracentesis Settings: specialised units in an intensive or semi‐intensive setting Intervention: plasma expander Comparison: no plasma expander | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Certainty of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No plasma expander | Plasma expander | |||||
| Recurrence of ascites mean follow‐up 126 days (30‐222) | Medium risk population | RR 1.30 (0.49 to 3.42) | 195 | ⊕⊝⊝⊝ | ||
| 155 per 1000 | 201 per 1000 | |||||
| Hypotension follow‐up 2 days | See comment | See comment | 23 (1) | There was a single trial with 0 events in each group. | ||
| Hyponatraemia mean follow‐up 57 days (1‐222) | Medium risk population | RR 0.53 (0.05 to 5.65) | 181 | ⊕⊝⊝⊝ | ||
| 130 per 1000 | 69 per 1000 | |||||
| * Assumed risk is the risk in comparison group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded 3 levels because of within study risk of bias: all trials were at high risk of bias (‐2 levels); imprecision: the required information size as calculated by GRADE not reached (‐1 levels) | ||||||
| Comparison of imprecision evaluation with GRADE based on the GRADE Handbook, with GRADE based on authors' choice of plausible relative risk reduction and multiplicity correction, and according to our Trial Sequential Analysis with a similar choice of plausible relative risk reduction and multiplicity correction, in addition to considering the choice of meta‐analytic model and diversity | |||||||
| Outcome | Proportion in control group | Relative risk reduction | Alpha | Beta | Diversity | Required information size (OIS or DARIS) | Downgrading of evidence for imprecision based on required information size |
| Recurrence of ascites ‐‐ GRADE Handbook | 15.5% | 25% | 5% | 20% | Not used | 2444 | One level |
| Recurrence of ascites ‐‐ GRADE plausible RRR | 15.5% | 10% | 2% | 20% | Not used | 20,980 | One level |
| Recurrence of ascites ‐‐ TSA | 15.5% | 10% | 2% | 20% | 51% | 43,013 | One level |
| Hypotension ‐‐ GRADE Handbook (1) | |||||||
| Hypotension ‐‐ GRADE plausible RRR (1) | |||||||
| Hypotension ‐‐ TSA (1) | |||||||
| Hyponatraemia ‐‐ GRADE Handbook | 13% | 25% | 5% | 20% | Not used | 2996 | One level |
| Hyponatraemia ‐‐ GRADE plausible RRR | 13% | 10% | 2% | 20% | Not used | 25,712 | One level |
| Hyponatraemia ‐‐ TSA | 13% | 10% | 2% | 20% | 10% | 28,526 | One level |
| (1) There was a single trial with 0 events in each group OIS: optimal information size; DARIS: diversity‐adjusted required information size; RRR: relative risk reduction; TSA: Trial Sequential Analysis | |||||||
| Comparison of imprecision evaluation with GRADE based on the GRADE Handbook, with GRADE based on authors' choice of plausible relative risk reduction and multiplicity correction, and according to our Trial Sequential Analysis with a similar choice of plausible relative risk reduction and multiplicity correction, in addition to considering the choice of meta‐analytic model and diversity | |||||||
| Outcome | Proportion in control group | Relative risk reduction | Alpha | Beta | Diversity | Required information size (OIS or DARIS) | Downgrading of evidence for imprecision based on required information size |
| All‐cause mortality ‐‐ GRADE Handbook | 18.2% | 25% | 5% | 20% | Not used | 2030 | One level |
| All‐cause mortality ‐‐ GRADE plausible RRR | 18.2% | 10% | 2.5% | 20% | Not used | 16,415 | One level |
| All‐cause mortality ‐‐ TSA | 18.2% | 10% | 2.5% | 20% | 0% | 16,415 | One level |
| Serious adverse events ‐‐ GRADE Handbook | 1.8% | 25% | 5% | 20% | Not used | 24,032 | One level |
| Serious adverse events ‐‐ GRADE plausible RRR | 1.8% | 5% | 2.5% | 20% | Not used | 809,313 | One level |
| Serious adverse events ‐‐ TSA | 1.8% | 5% | 2.5% | 20% | 0% | 809,313 | One level |
| Health‐related quality of life ‐‐ GRADE Handbook | No data | ||||||
| Health‐related quality of life ‐‐ GRADE plausible RRR | No data | ||||||
| Health‐related quality of life ‐‐ TSA | No data | ||||||
| Refractory ascites ‐‐ GRADE Handbook | No data | ||||||
| Refractory ascites ‐‐ GRADE plausible RRR | No data | ||||||
| Refractory ascites ‐‐ TSA | No data | ||||||
| Renal impairment ‐‐ GRADE Handbook | 5% | 25% | 5% | 20% | Not used | 8404 | One level |
| Renal impairment ‐‐ GRADE plausible RRR | 5% | 10% | 2.00% | 20% | Not used | 72,650 | One level |
| Renal impairment ‐‐ TSA | 5% | 10% | 2.00% | 20% | 0% | 72,651 | One level |
| Other liver‐related complications ‐‐ GRADE Handbook | 18.5% | 25% | 5% | 20% | Not used | 1986 | One level |
| Other liver‐related complications ‐‐ GRADE plausible RRR | 18.5% | 10% | 2.00% | 20% | Not used | 16,990 | One level |
| Other liver‐related complications ‐‐ TSA | 18.5% | 10% | 2.00% | 20% | 0% | 16,992 | One level |
| Non‐serious adverse events ‐‐ GRADE Handbook | 2.5% | 25% | 5% | 20% | Not used | 16,904 | One level |
| Non‐serious adverse events ‐‐ GRADE plausible RRR | 2.5% | 10% | 2.00% | 20% | Not used | 148,922 | One level |
| Non‐serious adverse events ‐‐ TSA | 2.5% | 10% | 2.00% | 20% | 0% | 148,925 | One level |
| OIS: optimal information size; DARIS: diversity‐adjusted required information size; RRR: relative risk reduction; TSA: Trial Sequential Analysis | |||||||
| Plasma expanders versus albumin for people with cirrhosis and large ascites treated with abdominal paracentesis: exploratory outcomes | ||||||
| Patient or population: cirrhotic participants with large ascites treated by paracentesis Settings: specialised units in an intensive or semi‐intensive setting Intervention: all plasma expanders except albumin Comparison: albumin | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Certainty of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Albumin | Experimental plasma expanders | |||||
| Recurrence of ascites mean follow‐up 169 days (5‐638) | Medium risk population | RR 1.14 (0.96 to 1.36) | 700 | ⊕⊝⊝⊝ | ||
| 363 per 1000 | 412 per 1000 | |||||
| Hypotension follow‐up 6 days | 88 per 1000 | 239 per 1000 | RR 2.71 (1.13 to 6.50) | 135 | Certainty of the evidence not assessed | |
| Hyponatraemia mean follow‐up 174 days (3‐638) | Medium risk population | RR 1.49 (1.03 to 2.14) | 1107 | ⊕⊝⊝⊝ | ||
| 73 per 1000 | 108 per 1000 | |||||
| Post‐paracentesis circulatory dysfunction mean follow‐up 100 days (6‐288) | Medium risk population | RR 1.98 (1.31 to 2.99) | 432 | ⊕⊝⊝⊝ | ||
| 148 per 1000 | 294 per 1000 | |||||
| * Assumed risk is the risk in comparison group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded 3 levels because of within study risk of bias: all trials were at high risk of bias (‐2 levels); imprecision: required information size as calculated by GRADE not reached (‐1 level) | ||||||
| Comparison of imprecision evaluation with GRADE based on the GRADE Handbook, with GRADE based on authors' choice of plausible relative risk reduction and multiplicity correction, and according to our Trial Sequential Analysis with a similar choice of plausible relative risk reduction and multiplicity correction, in addition to considering the choice of meta‐analytic model and diversity | |||||||
| Outcome | Proportion in control group | Relative risk reduction | Alpha | Beta | Diversity | Required information size (OIS or DARIS) | Downgrading of evidence for imprecision based on required information size |
| Recurrence of ascites ‐‐ GRADE Handbook | 36.3% | 25% | 5% | 20% | Not used | 824 | One level |
| Recurrence of ascites ‐‐ GRADE plausible RRR | 36.3% | 10% | 2% | 20% | Not used | 6882 | One level |
| Recurrence of ascites ‐‐ TSA | 36.3% | 10% | 2% | 20% | 3% | 7104 | One level |
| Hypotension ‐‐ GRADE Handbook | 8.8% | 25% | 5% | 20% | Not used | 4608 | One level |
| Hypotension ‐‐ GRADE plausible RRR | 8.8% | 10% | 2% | 20% | Not used | 39,712 | One level |
| Hypotension ‐‐ TSA (1) | |||||||
| Hyponatraemia ‐‐ GRADE Handbook | 7.3% | 25% | 5% | 20% | Not used | 5602 | One level |
| Hyponatraemia ‐‐ GRADE plausible RRR | 7.3% | 10% | 2% | 20% | Not used | 48,618 | One level |
| Hyponatraemia ‐‐ TSA | 7.3% | 10% | 2% | 20% | 0% | 48,620 | One level |
| Post‐paracentesis circulatory dysfunction ‐‐ GRADE Handbook | 14.8% | 25% | 5% | 20% | Not used | 2584 | One level |
| Post‐paracentesis circulatory dysfunction ‐‐ GRADE plausible RRR | 14.8% | 10% | 2% | 20% | Not used | 22,144 | One level |
| Post‐paracentesis circulatory dysfunction ‐‐ TSA | 14.8% | 10% | 2% | 20% | 0% | 22,146 | One level |
| (1) TSA non calculated because there was only one trial OIS: optimal information size; DARIS: diversity‐adjusted required information size; RRR: relative risk reduction; TSA: Trial Sequential Analysis | |||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 4 | 248 | Risk Ratio (M‐H, Random, 95% CI) | 0.52 [0.06, 4.83] |
| 1.1 Albumin | 3 | 158 | Risk Ratio (M‐H, Random, 95% CI) | 1.27 [0.75, 2.17] |
| 1.2 Ascites infusion | 1 | 90 | Risk Ratio (M‐H, Random, 95% CI) | 0.13 [0.02, 1.13] |
| 2 Serious adverse events Show forest plot | 2 | 108 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2.1 Albumin | 1 | 18 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2.2 Infusion of ascites | 1 | 90 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3 Renal impairment Show forest plot | 4 | 181 | Risk Ratio (M‐H, Random, 95% CI) | 0.32 [0.02, 5.88] |
| 4 Other liver‐related complications Show forest plot | 4 | 248 | Risk Ratio (M‐H, Random, 95% CI) | 1.61 [0.79, 3.27] |
| 4.1 Albumin | 3 | 158 | Risk Ratio (M‐H, Random, 95% CI) | 1.61 [0.76, 3.41] |
| 4.2 Infusion of ascitic fluid | 1 | 90 | Risk Ratio (M‐H, Random, 95% CI) | 1.58 [0.17, 14.53] |
| 5 Non‐serious adverse events Show forest plot | 3 | 158 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.32, 3.40] |
| 5.1 Albumin | 3 | 158 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.32, 3.40] |
| 6 Recurrence of ascites Show forest plot | 2 | 195 | Risk Ratio (M‐H, Random, 95% CI) | 1.30 [0.49, 3.42] |
| 6.1 Albumin | 1 | 105 | Risk Ratio (M‐H, Random, 95% CI) | 0.93 [0.43, 1.99] |
| 6.2 Ascites infusion | 1 | 90 | Risk Ratio (M‐H, Random, 95% CI) | 2.63 [0.61, 11.25] |
| 7 Hyponatraemia Show forest plot | 4 | 181 | Risk Ratio (M‐H, Random, 95% CI) | 0.53 [0.05, 5.65] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 4 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 Participants with partial paracentesis | 1 | 105 | Risk Ratio (M‐H, Random, 95% CI) | 1.27 [0.75, 2.17] |
| 1.2 Participants with total paracentesis | 3 | 143 | Risk Ratio (M‐H, Random, 95% CI) | 0.13 [0.02, 1.13] |
| 2 Renal impairment Show forest plot | 4 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.1 Participants with partial paracentesis | 1 | 105 | Risk Ratio (M‐H, Random, 95% CI) | 0.07 [0.00, 1.16] |
| 2.2 Participants with total paracentesis | 3 | 76 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.17, 6.70] |
| 3 Other liver‐related complications Show forest plot | 4 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 3.1 Participants with partial paracentesis | 1 | 105 | Risk Ratio (M‐H, Random, 95% CI) | 1.63 [0.57, 4.66] |
| 3.2 Participants with total paracentesis | 3 | 143 | Risk Ratio (M‐H, Random, 95% CI) | 1.59 [0.60, 4.18] |
| 4 Non‐serious adverse events Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 4.1 Participants with partial paracentesis | 1 | 105 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.22, 4.82] |
| 4.2 Participants with total paracentesis | 2 | 53 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.17, 6.70] |
| 5 Hyponatraemia Show forest plot | 4 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 5.1 Participants with partial paracentesis | 1 | 105 | Risk Ratio (M‐H, Random, 95% CI) | 0.19 [0.04, 0.80] |
| 5.2 Participants with total paracentesis | 3 | 76 | Risk Ratio (M‐H, Random, 95% CI) | 2.12 [0.21, 21.27] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 4 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 Up to 1 month | 3 | 143 | Risk Ratio (M‐H, Random, 95% CI) | 0.13 [0.02, 1.13] |
| 1.2 More than 1 month | 1 | 105 | Risk Ratio (M‐H, Random, 95% CI) | 1.27 [0.75, 2.17] |
| 2 Renal impairment Show forest plot | 3 | 158 | Risk Ratio (M‐H, Random, 95% CI) | 0.32 [0.02, 5.88] |
| 2.1 Up to 1 month | 2 | 53 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.17, 6.70] |
| 2.2 More than 1 month | 1 | 105 | Risk Ratio (M‐H, Random, 95% CI) | 0.07 [0.00, 1.16] |
| 3 Other liver‐related complications Show forest plot | 4 | 248 | Risk Ratio (M‐H, Random, 95% CI) | 1.61 [0.79, 3.27] |
| 3.1 Up to 1 month | 3 | 143 | Risk Ratio (M‐H, Random, 95% CI) | 1.59 [0.60, 4.18] |
| 3.2 More than 1 month | 1 | 105 | Risk Ratio (M‐H, Random, 95% CI) | 1.63 [0.57, 4.66] |
| 4 Non‐serious adverse events Show forest plot | 3 | 158 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.32, 3.40] |
| 4.1 Up to 1 month | 2 | 53 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.17, 6.70] |
| 4.2 More than 1 month | 1 | 105 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.22, 4.82] |
| 5 Hyponatraemia Show forest plot | 4 | 181 | Risk Ratio (M‐H, Random, 95% CI) | 0.53 [0.05, 5.65] |
| 5.1 Up to 1 month | 3 | 76 | Risk Ratio (M‐H, Random, 95% CI) | 2.12 [0.21, 21.27] |
| 5.2 More than 1 month | 1 | 105 | Risk Ratio (M‐H, Random, 95% CI) | 0.19 [0.04, 0.80] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 4 | 248 | Risk Ratio (M‐H, Random, 95% CI) | 0.52 [0.06, 4.83] |
| 1.1 Trials without for‐profit funding | 3 | 213 | Risk Ratio (M‐H, Random, 95% CI) | 0.52 [0.06, 4.83] |
| 1.2 Trials with for‐profit funding or unknown | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2 Renal impairment Show forest plot | 4 | 181 | Risk Ratio (M‐H, Random, 95% CI) | 0.32 [0.02, 5.88] |
| 2.1 Trials without for‐profit funding | 2 | 123 | Risk Ratio (M‐H, Random, 95% CI) | 0.07 [0.00, 1.16] |
| 2.2 Trials with for‐profit funding or unknown | 2 | 58 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.17, 6.70] |
| 3 Other liver‐related complications Show forest plot | 4 | 248 | Risk Ratio (M‐H, Random, 95% CI) | 1.61 [0.79, 3.27] |
| 3.1 Trials without for‐profit funding | 3 | 213 | Risk Ratio (M‐H, Random, 95% CI) | 1.62 [0.63, 4.19] |
| 3.2 Trials with for‐profit funding or unknown | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 1.59 [0.54, 4.67] |
| 4 Non‐serious adverse events Show forest plot | 3 | 158 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.32, 3.40] |
| 4.1 Trials without for‐profit funding | 2 | 123 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.22, 4.82] |
| 4.2 Trials with for‐profit funding or unknown | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.17, 6.70] |
| 5 Hyponatraemia Show forest plot | 4 | 181 | Risk Ratio (M‐H, Random, 95% CI) | 0.53 [0.05, 5.65] |
| 5.1 Trials without for‐profit funding | 2 | 123 | Risk Ratio (M‐H, Random, 95% CI) | 0.19 [0.04, 0.80] |
| 5.2 Trials with for‐profit funding or unknown | 2 | 58 | Risk Ratio (M‐H, Random, 95% CI) | 2.12 [0.21, 21.27] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 4 | 248 | Risk Ratio (M‐H, Random, 95% CI) | 0.49 [0.06, 3.76] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 4 | 248 | Risk Ratio (M‐H, Random, 95% CI) | 0.87 [0.28, 2.76] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 14 | 1014 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.82, 1.30] |
| 1.1 Dextran | 3 | 271 | Risk Ratio (M‐H, Random, 95% CI) | 1.28 [0.79, 2.06] |
| 1.2 Hydroxyethyl starch | 2 | 147 | Risk Ratio (M‐H, Random, 95% CI) | 1.16 [0.45, 3.02] |
| 1.3 Polygeline | 4 | 319 | Risk Ratio (M‐H, Random, 95% CI) | 1.12 [0.67, 1.89] |
| 1.4 Infusion of ascites | 4 | 137 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.61, 1.31] |
| 1.5 Mannitolum | 1 | 68 | Risk Ratio (M‐H, Random, 95% CI) | 0.88 [0.47, 1.66] |
| 1.6 Crystalloids | 1 | 72 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.07, 16.26] |
| 2 Serious adverse events Show forest plot | 2 | 118 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.10, 8.30] |
| 3 Renal impairment Show forest plot | 17 | 1107 | Risk Ratio (M‐H, Random, 95% CI) | 1.17 [0.71, 1.91] |
| 3.1 Dextran | 5 | 304 | Risk Ratio (M‐H, Random, 95% CI) | 0.85 [0.35, 2.08] |
| 3.2 Hydroxylethylstarch | 3 | 207 | Risk Ratio (M‐H, Random, 95% CI) | 1.01 [0.06, 15.90] |
| 3.3 Polygeline | 4 | 319 | Risk Ratio (M‐H, Random, 95% CI) | 1.53 [0.70, 3.38] |
| 3.4 Infusion of ascites | 4 | 137 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.22, 3.62] |
| 3.5 Mannitolum | 1 | 68 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3.6 Crystalloids | 1 | 72 | Risk Ratio (M‐H, Random, 95% CI) | 1.59 [0.28, 8.93] |
| 4 Other liver‐related complications Show forest plot | 16 | 1083 | Risk Ratio (M‐H, Random, 95% CI) | 1.10 [0.82, 1.48] |
| 4.1 Dextran | 5 | 304 | Risk Ratio (M‐H, Random, 95% CI) | 1.49 [0.98, 2.28] |
| 4.2 Hydroxyethyl starch | 3 | 207 | Risk Ratio (M‐H, Random, 95% CI) | 1.13 [0.69, 1.85] |
| 4.3 Polygeline | 4 | 319 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.43, 1.93] |
| 4.4 Infusion of ascites | 3 | 113 | Risk Ratio (M‐H, Random, 95% CI) | 0.23 [0.07, 0.73] |
| 4.5 Mannitolum | 1 | 68 | Risk Ratio (M‐H, Random, 95% CI) | 1.45 [0.61, 3.44] |
| 4.6 Crystalloids | 1 | 72 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.16, 7.10] |
| 5 Non‐serious adverse events Show forest plot | 14 | 977 | Risk Ratio (M‐H, Random, 95% CI) | 1.37 [0.66, 2.85] |
| 5.1 Dextran | 3 | 246 | Risk Ratio (M‐H, Random, 95% CI) | 0.48 [0.04, 5.08] |
| 5.2 Hydroxyethyl starch | 3 | 207 | Risk Ratio (M‐H, Random, 95% CI) | 2.26 [0.66, 7.71] |
| 5.3 Polygeline | 3 | 277 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.15, 5.47] |
| 5.4 Infusion of ascites | 4 | 137 | Risk Ratio (M‐H, Random, 95% CI) | 1.54 [0.41, 5.71] |
| 5.5 Mannitolum | 1 | 38 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 5.6 Crystalloids | 1 | 72 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 6 Recurrence of ascites Show forest plot | 12 | 700 | Risk Ratio (M‐H, Random, 95% CI) | 1.14 [0.96, 1.36] |
| 6.1 Dextran | 3 | 145 | Risk Ratio (M‐H, Random, 95% CI) | 0.85 [0.53, 1.37] |
| 6.2 Hydroxyethyl starch | 3 | 215 | Risk Ratio (M‐H, Random, 95% CI) | 1.49 [1.03, 2.15] |
| 6.3 Polygeline | 2 | 122 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.69, 1.54] |
| 6.4 Infusion of ascites | 2 | 78 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.46, 2.34] |
| 6.5 Mannitolum | 1 | 68 | Risk Ratio (M‐H, Random, 95% CI) | 0.9 [0.26, 3.07] |
| 6.6 Crystalloids | 1 | 72 | Risk Ratio (M‐H, Random, 95% CI) | 1.16 [0.57, 2.39] |
| 7 Hyponatraemia Show forest plot | 17 | 1107 | Risk Ratio (M‐H, Random, 95% CI) | 1.49 [1.03, 2.14] |
| 7.1 Dextran | 5 | 304 | Risk Ratio (M‐H, Random, 95% CI) | 1.44 [0.81, 2.58] |
| 7.2 Hydroxyethil starch | 3 | 207 | Risk Ratio (M‐H, Random, 95% CI) | 1.87 [0.40, 8.69] |
| 7.3 Polygeline | 4 | 319 | Risk Ratio (M‐H, Random, 95% CI) | 1.43 [0.83, 2.46] |
| 7.4 Infusion of ascites | 4 | 137 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.15, 6.93] |
| 7.5 Mannitolum | 1 | 68 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 7.6 Crystalloids | 1 | 72 | Risk Ratio (M‐H, Random, 95% CI) | 2.64 [0.55, 12.75] |
| 8 Post‐paracentesis circulatory dysfunction Show forest plot | 3 | 432 | Risk Ratio (M‐H, Random, 95% CI) | 1.98 [1.31, 2.99] |
| 8.1 Dextran | 1 | 142 | Risk Ratio (M‐H, Random, 95% CI) | 1.99 [1.04, 3.81] |
| 8.2 Hydroxylethyl starch | 1 | 75 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.14, 3.07] |
| 8.3 Polygeline | 1 | 147 | Risk Ratio (M‐H, Random, 95% CI) | 2.06 [1.03, 4.10] |
| 8.4 Crystalloids | 1 | 68 | Risk Ratio (M‐H, Random, 95% CI) | 2.92 [1.03, 8.26] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 14 | 1014 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [0.85, 1.35] |
| 1.1 Trials with participants without refractory ascites | 9 | 723 | Risk Ratio (M‐H, Random, 95% CI) | 1.15 [0.80, 1.66] |
| 1.2 Trials with participants with refractory ascites | 5 | 291 | Risk Ratio (M‐H, Random, 95% CI) | 1.01 [0.75, 1.37] |
| 2 Renal impairment Show forest plot | 17 | 1107 | Risk Ratio (M‐H, Random, 95% CI) | 1.17 [0.71, 1.92] |
| 2.1 Trials with participants without refractory ascites | 12 | 816 | Risk Ratio (M‐H, Random, 95% CI) | 1.24 [0.70, 2.20] |
| 2.2 Trials with participants with refractory ascites | 5 | 291 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.37, 2.65] |
| 3 Other liver‐related complications Show forest plot | 15 | 1033 | Risk Ratio (M‐H, Random, 95% CI) | 1.10 [0.82, 1.48] |
| 3.1 Trials with participants without refractory ascites | 11 | 766 | Risk Ratio (M‐H, Random, 95% CI) | 1.36 [1.03, 1.80] |
| 3.2 Trials with participants with refractory ascites | 4 | 267 | Risk Ratio (M‐H, Random, 95% CI) | 0.44 [0.16, 1.21] |
| 4 Non‐serious adverse events Show forest plot | 14 | 977 | Risk Ratio (M‐H, Random, 95% CI) | 1.37 [0.66, 2.85] |
| 4.1 Trials with participants without refractory ascites | 9 | 686 | Risk Ratio (M‐H, Random, 95% CI) | 1.47 [0.49, 4.36] |
| 4.2 Trials with participants with refractory ascites | 5 | 291 | Risk Ratio (M‐H, Random, 95% CI) | 1.30 [0.49, 3.47] |
| 5 Recurrence of ascites Show forest plot | 12 | 722 | Risk Ratio (M‐H, Random, 95% CI) | 1.14 [0.97, 1.34] |
| 5.1 Trials with participants without refractory ascites | 9 | 487 | Risk Ratio (M‐H, Random, 95% CI) | 1.10 [0.90, 1.35] |
| 5.2 Trials with participants with refractory ascites | 4 | 235 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [0.86, 1.66] |
| 6 Hyponatraemia Show forest plot | 17 | 1107 | Risk Ratio (M‐H, Random, 95% CI) | 1.49 [1.03, 2.14] |
| 6.1 Trials with participants without refractory ascites | 12 | 816 | Risk Ratio (M‐H, Random, 95% CI) | 1.53 [1.03, 2.27] |
| 6.2 Trials with participants with refractory ascites | 5 | 291 | Risk Ratio (M‐H, Random, 95% CI) | 1.29 [0.51, 3.26] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 14 | 1014 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [0.85, 1.35] |
| 1.1 Participants with partial paracentesis | 2 | 109 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.59, 1.65] |
| 1.2 Participants with total paracentesis | 12 | 905 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.84, 1.41] |
| 2 Renal impairment Show forest plot | 16 | 1039 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.60, 1.82] |
| 2.1 Participants with partial paracentesis | 3 | 169 | Risk Ratio (M‐H, Random, 95% CI) | 1.05 [0.07, 15.68] |
| 2.2 Participants with total paracentesis | 13 | 870 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.59, 1.84] |
| 3 Other liver‐related complications Show forest plot | 15 | 1033 | Risk Ratio (M‐H, Random, 95% CI) | 1.10 [0.82, 1.48] |
| 3.1 Participants with partial paracentesis | 3 | 169 | Risk Ratio (M‐H, Random, 95% CI) | 1.54 [0.76, 3.11] |
| 3.2 Participants with total paracentesis | 12 | 864 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.67, 1.42] |
| 4 Non‐serious adverse events Show forest plot | 14 | 977 | Risk Ratio (M‐H, Random, 95% CI) | 1.37 [0.66, 2.85] |
| 4.1 Participants with partial paracentesis | 2 | 98 | Risk Ratio (M‐H, Random, 95% CI) | 8.5 [0.46, 157.71] |
| 4.2 Participants with total paracentesis | 12 | 879 | Risk Ratio (M‐H, Random, 95% CI) | 1.22 [0.57, 2.58] |
| 5 Recurrences of ascites Show forest plot | 12 | 702 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.93, 1.32] |
| 5.1 Participants with partial paracentesis | 3 | 169 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.28 [0.72, 2.26] |
| 5.2 Participants with total paracentesis | 9 | 533 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.09 [0.91, 1.30] |
| 6 Hyponatraemia Show forest plot | 17 | 1107 | Risk Ratio (M‐H, Random, 95% CI) | 1.49 [1.03, 2.14] |
| 6.1 Participants with partial paracentesis | 3 | 169 | Risk Ratio (M‐H, Random, 95% CI) | 1.00 [0.29, 3.51] |
| 6.2 Participants with total paracentesis | 14 | 938 | Risk Ratio (M‐H, Random, 95% CI) | 1.54 [1.05, 2.26] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 14 | 1014 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.82, 1.30] |
| 1.1 Up to 1 month | 5 | 458 | Risk Ratio (M‐H, Random, 95% CI) | 1.59 [0.47, 5.33] |
| 1.2 More than 1 month | 9 | 556 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.80, 1.29] |
| 2 Serious adverse events Show forest plot | 2 | 118 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.12, 6.50] |
| 2.1 Up to 1 month | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 7.81] |
| 2.2 More than 1 month | 1 | 68 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.38 [0.10, 56.53] |
| 3 Renal impairment Show forest plot | 17 | 1107 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.13 [0.70, 1.83] |
| 3.1 Up to 1 month | 8 | 551 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.13 [0.56, 2.25] |
| 3.2 More than 1 month | 9 | 556 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.14 [0.58, 2.22] |
| 4 Other liver‐related complications Show forest plot | 15 | 1033 | Risk Ratio (M‐H, Random, 95% CI) | 1.08 [0.79, 1.48] |
| 4.1 Up to 1 month | 7 | 501 | Risk Ratio (M‐H, Random, 95% CI) | 1.17 [0.64, 2.16] |
| 4.2 More than 1 month | 8 | 532 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.65, 1.53] |
| 5 Non‐serious adverse events Show forest plot | 14 | 977 | Risk Ratio (M‐H, Random, 95% CI) | 1.33 [0.67, 2.63] |
| 5.1 Up to 1 month | 6 | 484 | Risk Ratio (M‐H, Random, 95% CI) | 2.20 [0.73, 6.59] |
| 5.2 More than 1 month | 8 | 493 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.41, 2.32] |
| 6 Recurrence of ascites Show forest plot | 12 | 702 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.93, 1.32] |
| 6.1 Up to 1 month | 3 | 96 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.07 [1.12, 3.83] |
| 6.2 More than 1 month | 9 | 606 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.86, 1.24] |
| 7 Hyponatraemia Show forest plot | 17 | 1107 | Risk Ratio (M‐H, Random, 95% CI) | 1.49 [1.03, 2.14] |
| 7.1 Up to 1 month | 8 | 551 | Risk Ratio (M‐H, Random, 95% CI) | 1.64 [1.01, 2.68] |
| 7.2 More than 1 month | 9 | 556 | Risk Ratio (M‐H, Random, 95% CI) | 1.31 [0.76, 2.28] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 14 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 Trials without for‐profit funding | 6 | 357 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [0.79, 1.81] |
| 1.2 Trials with for‐profit funding or unknown | 8 | 657 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.73, 1.28] |
| 2 Renal impairment Show forest plot | 17 | 1107 | Risk Ratio (M‐H, Random, 95% CI) | 1.17 [0.71, 1.92] |
| 2.1 Trials without for‐profit funding | 6 | 357 | Risk Ratio (M‐H, Random, 95% CI) | 1.46 [0.72, 2.97] |
| 2.2 Trials with for‐profit funding or unknown | 11 | 750 | Risk Ratio (M‐H, Random, 95% CI) | 0.95 [0.48, 1.90] |
| 3 Other liver‐related complications Show forest plot | 16 | 1083 | Risk Ratio (M‐H, Random, 95% CI) | 1.23 [0.97, 1.56] |
| 3.1 Trials without for‐profit funding | 6 | 357 | Risk Ratio (M‐H, Random, 95% CI) | 1.42 [1.03, 1.97] |
| 3.2 Trials with for‐profit funding or unknown | 10 | 726 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.69, 1.50] |
| 4 Non‐serious adverse events Show forest plot | 14 | 977 | Risk Ratio (M‐H, Random, 95% CI) | 1.38 [0.66, 2.85] |
| 4.1 Trials without for‐profit funding | 4 | 274 | Risk Ratio (M‐H, Random, 95% CI) | 0.62 [0.12, 3.05] |
| 4.2 Trials with for‐profit funding or unknown | 10 | 703 | Risk Ratio (M‐H, Random, 95% CI) | 1.70 [0.75, 3.85] |
| 5 Recurrence of ascites Show forest plot | 12 | 700 | Risk Ratio (M‐H, Random, 95% CI) | 1.14 [0.96, 1.36] |
| 5.1 Trials without for‐profit funding | 5 | 307 | Risk Ratio (M‐H, Random, 95% CI) | 1.16 [0.96, 1.42] |
| 5.2 Trials with for‐profit funding or unknown | 7 | 393 | Risk Ratio (M‐H, Random, 95% CI) | 1.13 [0.79, 1.60] |
| 6 Hyponatraemia Show forest plot | 17 | 1107 | Risk Ratio (M‐H, Random, 95% CI) | 1.49 [1.03, 2.14] |
| 6.1 Trials without for‐profit funding | 6 | 357 | Risk Ratio (M‐H, Random, 95% CI) | 1.48 [0.79, 2.77] |
| 6.2 Trials with for‐profit funding or unknown | 11 | 750 | Risk Ratio (M‐H, Random, 95% CI) | 1.49 [0.95, 2.34] |
| 7 Post‐paracentesis circulatory dysfunction Show forest plot | 3 | 432 | Risk Ratio (M‐H, Random, 95% CI) | 1.93 [1.12, 3.32] |
| 7.1 Trials without for‐profit funding | 2 | 143 | Risk Ratio (M‐H, Random, 95% CI) | 1.56 [0.37, 6.51] |
| 7.2 Trials with for‐profit funding or unknown | 1 | 289 | Risk Ratio (M‐H, Random, 95% CI) | 2.02 [1.26, 3.24] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 14 | 1016 | Risk Ratio (M‐H, Random, 95% CI) | 1.29 [1.04, 1.60] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality Show forest plot | 14 | 1016 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.96, 1.03] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Other liver‐related complications Show forest plot | 1 | 20 | Risk Ratio (M‐H, Random, 95% CI) | 3.00 [0.14, 65.90] |
| 2 Non‐serious adverse events Show forest plot | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 15.0 [0.97, 231.84] |
| 3 Recurrence of ascites Show forest plot | 1 | 20 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.69, 1.18] |
