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Base de datos Cochrane de Revisiones Sistemáticas Revisión - Intervención

Tratamiento para la ascitis en pacientes adultos con cirrosis hepática descompensada: un metanálisis en red

Declaraciones de intereses de los autores

Versión publicada: 16 enero 2020 Historial de versiones

https://doi.org/10.1002/14651858.CD013123.pub2
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Resumen

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Antecedentes

Aproximadamente el 20% de los pacientes con cirrosis desarrollan ascitis. Se dispone de varios tratamientos diferentes; entre ellos, la paracentesis más reposición de líquidos, las derivaciones portosistémicas intrahepáticas transyugulares, los antagonistas de la aldosterona y los diuréticos de asa. Sin embargo, hay incertidumbre en cuanto a su eficacia relativa.

Objetivos

Comparar los efectos beneficiosos y perjudiciales de los diferentes tratamientos para la ascitis en pacientes con cirrosis hepática descompensada mediante un metanálisis en red y generar clasificaciones de los diferentes tratamientos para la ascitis según su seguridad y eficacia.

Métodos de búsqueda

Se realizaron búsquedas en CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, la International Clinical Trials Registry Platform de la Organización Mundial de la Salud y en registros de ensayos hasta mayo de 2019 para identificar ensayos clínicos aleatorizados en pacientes con cirrosis y ascitis.

Criterios de selección

Solo se incluyeron los ensayos clínicos aleatorizados (independientemente del idioma, el cegamiento o el estado de publicación) en pacientes adultos con cirrosis y ascitis. Se excluyeron los ensayos clínicos aleatorizados en los que los participantes se habían sometido previamente a un trasplante hepático.

Obtención y análisis de los datos

Se realizó un metanálisis en red con OpenBUGS mediante métodos bayesianos y se calcularon el odds ratio, el cociente de tasas y el cociente de riesgos instantáneos (CRI) con intervalos de confianza (IC) del 95% sobre la base de un análisis de casos disponibles, según la guía del National Institute of Health y de la Care Excellence Decision Support Unit.

Resultados principales

En la revisión se incluyeron 49 ensayos clínicos aleatorizados (3521 participantes). Se incluyeron 42 ensayos (2870 participantes) en uno o más resultados de la revisión. Los ensayos que proporcionaron la información incluyeron a pacientes con cirrosis debida a etiologías variadas, sin otras características de descompensación, que principalmente presentaban ascitis grado 3 (grave), recurrente o refractaria. El seguimiento en los ensayos varió de 0,1 a 84 meses. Todos los ensayos tenían un alto riesgo de sesgo y la certeza general de la evidencia fue baja o muy baja.

Aproximadamente el 36,8% de los participantes sometidos a paracentesis más reposición de líquidos (grupo de referencia, el tratamiento estándar actual) murieron en el transcurso de 11 meses. No hubo evidencia de diferencias en la mortalidad, los eventos adversos ni el trasplante de hígado en los pacientes que recibieron diferentes intervenciones en comparación con la paracentesis más reposición de líquidos (evidencia de certeza muy baja). La resolución de la ascitis en el seguimiento máximo fue mayor con la derivación portosistémica intrahepática transyugular (CRI 9,44; IC del 95%: 1,93 a 62,68) y el agregado de antagonistas de aldosterona a la paracentesis más reposición de líquidos (CRI 30,63; IC del 95%: 5,06 a 692,98) en comparación con la paracentesis más reposición de líquidos (evidencia de certeza muy baja). Los antagonistas de la aldosterona más los diuréticos de asa tuvieron una mayor tasa de otros eventos de descompensación como encefalopatía hepática, síndrome hepatorrenal y hemorragia de las várices en comparación con la paracentesis más la reposición de líquidos (cociente de tasas 2,04; IC del 95%: 1,37 a 3,10) (evidencia de certeza muy baja).

Ninguno de los ensayos en los que se utilizó la paracentesis más reposición de líquidos informaron sobre la calidad de vida relacionada con la salud ni la recuperación sintomática de la ascitis.

Financiación: la fuente de financiación de cuatro ensayos fueron las industrias que se beneficiarían de los resultados de los estudios; 24 ensayos no recibieron financiación adicional o fueron financiados por organizaciones neutrales; y la fuente de financiación de los 21 ensayos restantes no estuvo clara.

Conclusiones de los autores

Sobre la base de evidencia de certeza muy baja, existe una considerable incertidumbre acerca de si las intervenciones para la ascitis en pacientes con cirrosis hepática descompensada disminuyen la mortalidad, los eventos adversos o el trasplante de hígado en comparación con la paracentesis más reposición de líquidos en pacientes con cirrosis hepática descompensada y ascitis. En función de la evidencia de certeza muy baja, la derivación portosistémica intrahepática transyugular y el agregado de antagonistas de la aldosterona a la paracentesis más reposición de líquidos podría mejorar la resolución de la ascitis en comparación con la paracentesis más reposición de líquidos. En función de la evidencia de certeza muy baja, los antagonistas de la aldosterona más diuréticos de asa podrían aumentar la tasa de descompensación en comparación con la paracentesis más reposición de líquidos.

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Resumen en términos sencillos

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Tratamientos para la ascitis en pacientes con enfermedad hepática avanzada

¿Cuál es el objetivo de esta Revisión Cochrane?
Determinar cuál es el mejor tratamiento disponible para la ascitis (acumulación anormal de líquido en el abdomen) en pacientes con enfermedad hepática avanzada (cirrosis hepática o cicatrización del hígado en etapa avanzada con complicaciones). Los pacientes con cirrosis y ascitis tienen un riesgo importante de muerte. Por lo tanto, es importante tratar a estos pacientes, pero actualmente no están claros los efectos beneficiosos y perjudiciales de los diferentes tratamientos disponibles. Los autores de esta revisión recopilaron y analizaron todos los estudios de investigación relevantes con el objetivo de encontrar cuál es el mejor tratamiento. Se encontraron 49 ensayos controlados aleatorizados (estudios en los que los participantes se asignan al azar a uno de dos grupos de tratamiento). Durante el análisis de los datos, los autores utilizaron los métodos estándar de Cochrane, que permiten la comparación de sólo dos tratamientos a la vez. Los autores también utilizaron técnicas avanzadas que permiten la comparación de múltiples tratamientos de forma simultánea (lo que habitualmente se denomina "metanálisis en red [o indirecto]").

Fecha de la búsqueda bibliográfica
mayo de 2019

Mensajes clave
Ninguno de los estudios se realizó sin deficiencias, y por ello, hay una gran incertidumbre en los resultados. Aproximadamente uno de tres participantes con cirrosis y ascitis de los ensayos que recibieron el tratamiento estándar de drenaje de líquidos (paracentesis) más reposición de líquidos murieron en el transcurso de los 11 meses de tratamiento. En 21 estudios no estuvo clara la fuente de financiación y organizaciones comerciales financiaron cuatro estudios. No hubo preocupaciones en cuanto a la fuente de financiación de los 24 ensayos restantes.

¿Qué se estudió en la revisión?
Esta revisión consideró a pacientes adultos de cualquier sexo, edad y origen étnico, con enfermedad hepática avanzada debido a diversas causas y ascitis. Los participantes recibieron tratamientos diferentes para la ascitis. Los autores excluyeron los estudios realizados en pacientes que habían recibido previamente un trasplante de hígado. La edad media de los participantes, cuando se informó, varió entre 43 y 64 años. Los tratamientos utilizados en los ensayos incluyeron paracentesis más reposición de líquidos (considerado actualmente el tratamiento estándar), diferentes clases de diuréticos (fármacos que aumentan la eliminación líquidos a través de la orina) y la derivación portosistémica intrahepática transyugular (un canal artificial que conecta los diferentes vasos sanguíneos que transportan sangre desoxigenada [sistema venoso]) dentro del hígado para reducir la presión acumulada en el sistema venoso portal, uno de los dos sistemas venosos que drena el hígado. Los autores de la revisión querían reunir y analizar datos sobre la muerte (porcentaje de muertes en el seguimiento máximo), la calidad de vida, los eventos adversos graves y no graves, el tiempo transcurrido hasta el trasplante de hígado, la resolución de la ascitis y el desarrollo de otras complicaciones de la enfermedad hepática avanzada.

¿Cuáles son los principales resultados de la revisión?
Los 49 estudios incluyeron un escaso número de participantes (3521 participantes). Los datos de los estudios fueron escasos. Cuarenta y dos estudios con 2870 participantes proporcionaron datos para los análisis. El seguimiento de los participantes de los ensayos varió desde menos de una semana hasta siete años. La revisión muestra que hay evidencia de certeza baja o muy baja de lo siguiente:

‐ Aproximadamente uno de tres pacientes con cirrosis y ascitis que recibieron el tratamiento estándar de drenaje de líquidos (paracentesis) más reposición de líquidos murieron en el transcurso de 11 meses.
‐ Ninguna de las intervenciones disminuyó el porcentaje de muertes, el número de complicaciones ni el trasplante de hígado en comparación con la paracentesis más la reposición de líquidos.
‐ La derivación portosistémica intrahepática transyugular puede ser nueve veces más efectiva en la resolución de la ascitis en comparación con la paracentesis más el reemplazo de líquidos.
‐ Añadir antagonistas de la aldosterona (una clase de diuréticos) puede ser 30 veces más efectivo en la resolución de la ascitis en comparación con la paracentesis más el reemplazo de líquidos.
‐ El uso de antagonistas de la aldosterona más diuréticos de asa (otra clase de diuréticos) como sustituto de la paracentesis más el reemplazo de líquidos puede duplicar el desarrollo de otras complicaciones hepáticas de la cirrosis.
‐ Ninguno de los ensayos que compararon otros tratamientos con la paracentesis más reposición de líquidos informó sobre la calidad de vida relacionada con la salud ni la recuperación sintomática de la ascitis.
‐ Se necesitan ensayos futuros bien diseñados para determinar el mejor tratamiento para los pacientes con cirrosis y ascitis.

Conclusiones de los autores

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Implicaciones para la práctica

Sobre la base de evidencia de certeza muy baja, existe una incertidumbre considerable acerca de si otras intervenciones disminuyen la mortalidad, los eventos adversos o el trasplante de hígado en comparación con la paracentesis más reposición de líquidos en pacientes con cirrosis hepática descompensada y ascitis. En función de la evidencia de certeza muy baja, la derivación portosistémica intrahepática transyugular y el agregado de antagonistas de la aldosterona a la paracentesis más reposición de líquidos podría mejorar la resolución de la ascitis en comparación con la paracentesis más reposición de líquidos. En función de la evidencia de certeza muy baja, los antagonistas de la aldosterona más diuréticos de asa podrían aumentar la tasa de descompensación en comparación con la paracentesis más reposición de líquidos.

Implicaciones para la investigación

Se necesitan más ensayos clínicos aleatorizados bien diseñados. Los siguientes son algunos aspectos del diseño de los ensayos clínicos aleatorizados.

Diseño del estudio: ensayo clínico paralelo y aleatorizado

Participantes: pacientes con cirrosis hepática y ascitis grado 3 o refractaria a los diuréticos

Intervenciones/control: derivación portosistémica intrahepática transyugular versus diuréticos más paracentesis más reemplazo de líquidos versus paracentesis más reemplazo de líquidos.

Medidas de resultado:

Resultado principal: mortalidad a medio plazo (mortalidad por todas las causas al año)

Resultados secundarios: calidad de vida relacionada con la salud, eventos de descompensación, eventos adversos, resolución de la ascitis y medidas de utilización de los recursos, que incluyen la duración de la estancia hospitalaria, los costes

Duración mínima del seguimiento: un año

Tamaño de la muestra:

Para un ensayo clínico aleatorizado simple de dos brazos paralelos, se requiere el tamaño de la muestra necesario para detectar o rechazar una reducción del riesgo relativo del 20% en el grupo experimental a partir de una proporción del grupo control del 36,8% de mortalidad, con un error tipo I del 5% y un error tipo II del 20%, 1282 participantes.

Otros aspectos:

Los ensayos se deben diseñar y realizar según la declaración SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) (Chan 2013) y la declaración CONSORT (Schulz 2010).

Summary of findings

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Summary of findings for the main comparison.

Treatment for ascites in people with decompensated liver cirrhosis

Patient or population: people with liver cirrhosis and ascites
Settings: secondary or tertiary care
Intervention: various interventions
Comparison: paracentesis plus fluid replacement
Follow‐up period: 0.1 to 84 months
Network geometry plots:Figure 1

Outcomes

Aldosterone antagonists plus loop diuretics

Paracentesis plus systemic vasoconstrictors

Aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement

Transjugular intrahepatic portosystemic shunt

Mortality at maximal follow‐up

Paracentesis plus fluid replacement
368 per 1000
(36.8%)

HR 1.05
(0.70 to 1.69)
Network estimate

18 more per 1000
(109 fewer to 253 more)

HR 1.64
(0.46 to 6.32)
Network estimate

235 more per 1000
(200 fewer to 632 more)

HR 1.24
(0.62 to 2.59)
Network estimate

88 more per 1000
(141 fewer to 587 more)

HR 0.84
(0.60 to 1.18)
Network estimate

59 fewer per 1000
(148 fewer to 65 more)

Very low1,2,3

Very low1,2,3

Very low1,2,3

Very low1,2,3

Based on 211 participants (4 RCTs)

Based on 165 participants (5 RCTs)

No direct RCT

Based on 452 participants (7 RCTs)

Serious adverse events (number of events)

Paracentesis plus fluid replacement
0 per 1000
(0 per 100 participants)

Rate ratio 1.30
(0.27 to 6.99)
Direct estimate

Not estimable

‐

‐

Not estimable

(10 serious adverse events in 35 participants)

Very low1,2,3

Very low1,2,3

Based on 41 participants (1 RCT)

Based on 70 participants (1 RCT)

Any adverse events (number of people)

Paracentesis plus fluid replacement
100 per 1000
(10%)

OR 3.54
(0.43 to 27.41)
Network estimate

182 more per 1000
(54 fewer to 653 more)

OR 1.63
(0.30 to 11.66)
Network estimate

53 more per 1000
(68 fewer to 464 more)

‐

‐

Very low1,2,3

Very low1,2,3

Based on 84 participants (2 RCTs)

Based on 145 participants (4 RCTs)

Any adverse events (number of events)

Paracentesis plus fluid replacement
118 per 1000
(11.8 per 100 participants)

Rate ratio 4.12
(0.87 to 34.02)
Network estimate

367 more per 1000
(15 fewer to 3885 more)

Rate ratio 1.37
(0.36 to 5.82)
Network estimate

43 more per 1000
(76 fewer to 567 more)

‐

‐

Very low1,2,3

Very low1,2,3

Based on 31 participants (1 RCT)

Based on 25 participants (1 RCT)

Liver transplantation at maximal follow‐up

Paracentesis plus fluid replacement
121 per 1000
(12.1%)

‐

HR 1.08
(0.11 to 10.35)
Network estimate

10 more per 1000
(108 fewer to 879 more)

‐

HR 0.87
(0.52 to 1.44)
Network estimate

15 fewer per 1000
(58 fewer to 54 more)

Very low1,2,3

Very low1,2,3

Based on 145 participants (4 RCTs)

Based on 427 participants (6 RCT)

Resolution of ascites at maximal follow‐up (by ultrasound)

Paracentesis plus fluid replacement
158 per 1000
(15.8%)

HR 1.10
(0.12 to 10.74)
Network estimate

16 more per 1000
(140 fewer to 842 more)

‐

HR 1.17
(0.01 to 98.79)
Network estimate

27 more per 1000
(156 fewer to 842 more)

HR 9.44
(1.93 to 62.68)
Network estimate

842 more per 1000
(147 more to 842 more)

Very low1,2,3,4

Very low1,2,3,4

Very low1,2,4

Based on 125 participants (3 RCTs)

No direct RCT

Based on 392 participants (6 RCTs)

Other features of decompensation at maximal follow‐up

Paracentesis plus fluid replacement
439 per 1000
(43.9 per 100 participants)

Rate ratio 2.04
(1.37 to 3.10)
Network estimate

458 more per 1000
(164 more to 922 more)

Rate ratio 0.76
(0.14 to 3.61)
Network estimate

107 fewer per 1000
(377 fewer to 1144 more)

Rate ratio 1.04
(0.56 to 1.93)
Network estimate

16 more per 1000
(195 fewer to 409 more)

Rate ratio 1.17
(0.92 to 1.49)
Network estimate

76 more per 1000
(33 fewer to 217 more)

Very low1,2,4

Very low1,2,3,4

Very low1,2,3,4

Very low1,2,3,4

Based on 242 participants (4 RCTs)

Based on 114 participants (3 RCTs)

No direct RCT

Based on 452 participants (7 RCTs)

*Ranking was not provided because of the considerable uncertainty in the ranking.
CrI: Credible interval; OR: Odds Ratio; HR: Hazard Ratio.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

1Downgraded one level for risk of bias because the trial(s) included in the analysis was/were at high risk of bias
2Downgraded one level for imprecision because the sample size was small
3Downgraded one level for imprecision because the credible intervals were wide (included clinical benefit and harms)
4Downgraded one level for inconsistency because there was evidence of statistical heterogeneity

Figure 1
A high resolution version of this image can be found at: https://doi.org/10.5281/zenodo.3604788..The network plots showing the outcomes for which network meta‐analysis was performed. The size of the node (circle) provides a measure of the number of trials in which the particular Intervention was included as one of the intervention groups. The thickness of the line provides a measure of the number of direct comparisons between two nodes (Interventions). A higher resolution image of this picture is available at: http://doi.org/10.5281/zenodo.3531818.Abbreviations Alb = Albumin
 AldoAnt = Aldosterone antagonists
 Fluid = Fluid replacement
 LoopD = Loop diuretics
 No active treatment = No active treatment
 OsmoD = Osmotic diuretics
 Paracen = Paracentesis
 PVShunt = Peritoneovenous shunt
 Reinf = Reinfusion
 Vasocons = Systemic vasoconstrictors
 Vasodil = Systemic vasodilator
 ThiazD = Thiazide diuretics
 TIPS = Transjugular intrahepatic portosystemic shunt

A high resolution version of this image can be found at: https://doi.org/10.5281/zenodo.3604788..

The network plots showing the outcomes for which network meta‐analysis was performed. The size of the node (circle) provides a measure of the number of trials in which the particular Intervention was included as one of the intervention groups. The thickness of the line provides a measure of the number of direct comparisons between two nodes (Interventions). A higher resolution image of this picture is available at: http://doi.org/10.5281/zenodo.3531818.

Abbreviations

Alb = Albumin
AldoAnt = Aldosterone antagonists
Fluid = Fluid replacement
LoopD = Loop diuretics
No active treatment = No active treatment
OsmoD = Osmotic diuretics
Paracen = Paracentesis
PVShunt = Peritoneovenous shunt
Reinf = Reinfusion
Vasocons = Systemic vasoconstrictors
Vasodil = Systemic vasodilator
ThiazD = Thiazide diuretics
TIPS = Transjugular intrahepatic portosystemic shunt

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Summary of findings 2.

Treatment for ascites in people with decompensated liver cirrhosis

Patient or population: people with liver cirrhosis and ascites
Settings: secondary or tertiary care
Intervention: various interventions
Comparison: paracentesis plus fluid replacement
Follow‐up period: 0.1 to 84 months
Network geometry plots:Figure 1

Interventions

Relative effect
(95% CrI)

Anticipated absolute effect* (95% CrI)

Quality of evidence

Paracentesis plus fluid replacement

Various interventions

Difference

Mortality at maximal follow‐up
Total studies: 32
Total participants: 2448

Paracentesis plus fluid replacement

Reference

Aldosterone antagonists plus loop diuretics
(4 RCTs; 211 participants)

HR 1.05
(0.70 to 1.69)
Network estimate

368 per 1000

387 per 1000
(260 to 621)

18 more per 1000
(109 fewer to 253 more)

Very low1,2,3

Paracentesis plus systemic vasoconstrictors
(5 RCTs; 165 participants)

HR 1.64
(0.46 to 6.32)
Network estimate

368 per 1000

604 per 1000
(168 to 1000)

235 more per 1000
(200 fewer to 632 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement
(No direct RCT)

HR 1.24
(0.62 to 2.59)
Network estimate

368 per 1000

457 per 1000
(227 to 955)

88 more per 1000
(141 fewer to 587 more)

Very low1,2,3

Transjugular intrahepatic portosystemic shunt
(7 RCTs; 452 participants)

HR 0.84
(0.60 to 1.18)
Network estimate

368 per 1000

309 per 1000
(221 to 433)

59 fewer per 1000
(148 fewer to 65 more)

Very low1,2,3

No active treatment
(No direct RCT)

HR 1.66
(0.46 to 6.99)
Network estimate

368 per 1000

611 per 1000
(170 to 1000)

243 more per 1000
(199 fewer to 632 more)

Very low1,2,3

Loop diuretics
(No direct RCT)

HR 0.71
(0.23 to 2.16)
Network estimate

368 per 1000

263 per 1000
(84 to 797)

105 fewer per 1000
(284 fewer to 429 more)

Very low1,2,3

Paracentesis plus reinfusion
(1 RCT; 24 participants)

HR 0.77
(0.23 to 2.68)
Network estimate

368 per 1000

284 per 1000
(84 to 987)

84 fewer per 1000
(285 fewer to 619 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus albumin
(No direct RCT)

HR 1.06
(0.57 to 2.16)
Network estimate

368 per 1000

392 per 1000
(209 to 795)

23 more per 1000
(159 fewer to 427 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus peritoneovenous shunt
(No direct RCT)

HR 0.97
(0.40 to 2.43)
Network estimate

368 per 1000

358 per 1000
(148 to 894)

10 fewer per 1000
(221 fewer to 526 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors
(No direct RCT)

HR 0.42
(0.15 to 1.22)
Network estimate

368 per 1000

153 per 1000
(55 to 450)

215 fewer per 1000
(313 fewer to 82 more)

Very low1,2,3

Aldosterone antagonists
(No direct RCT)

HR 1.92
(0.24 to 20.64)
Network estimate

368 per 1000

708 per 1000
(90 to 1000)

340 more per 1000
(278 fewer to 632 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus paracentesis plus fluid replacement
(No direct RCT)

HR 1.11
(0.02 to 39.77)
Network estimate

368 per 1000

408 per 1000
(9 to 1000)

40 more per 1000
(360 fewer to 632 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus systemic vasodilator
(No direct RCT)

HR 0.61
(0.02 to 9.17)
Network estimate

368 per 1000

226 per 1000
(9 to 1000)

142 fewer per 1000
(360 fewer to 632 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus systemic vasodilator
(No direct RCT)

HR 0.62
(0.03 to 9.10)
Network estimate

368 per 1000

228 per 1000
(12 to 1000)

140 fewer per 1000
(357 fewer to 632 more)

Very low1,2,3

Systemic vasoconstrictors plus albumin
(No direct RCT)

HR 2.62
(0.41 to 19.28)
Network estimate

368 per 1000

965 per 1000
(151 to 1000)

596 more per 1000
(218 fewer to 632 more)

Very low1,2,3

Serious adverse events (number of people)

None of the trials with paracentesis plus fluid replacement as an intervention reported this outcome

Serious adverse events (number of events)
Total studies: 1
Total participants: 41

Paracentesis plus fluid replacement

Reference

Aldosterone antagonists plus loop diuretics
(1 RCT; 41 participants)

Rate ratio 1.30
(0.27 to 6.99)
Direct estimate

0 per 1000

Not estimable

Very low1,2,3

Transjugular intrahepatic portosystemic shunt

(1 RCT; 70 participants)

Not estimable

(10 serious adverse events in 35 participants)

0 per 1000

Not estimable

Very low1,2,3

Health‐related quality of life

None of the trials with paracentesis plus fluid replacement as an intervention reported this outcome

Any adverse events (number of people)
Total studies: 6
Total participants: 229

Paracentesis plus fluid replacement

Reference

Paracentesis plus systemic vasoconstrictors
(4 RCTs; 145 participants)

OR 1.63
(0.30 to 11.66)
Network estimate

100 per 1000

153 per 1000
(32 to 564)

53 more per 1000
(68 fewer to 464 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics
(2 RCT; 84 participants)

OR 3.54
(0.43 to 27.41)
Network estimate

100 per 1000

282 per 1000
(46 to 753)

182 more per 1000
(54 fewer to 653 more)

Very low1,2,3

Any adverse events (number of events)
Total studies: 3
Total participants: 116

Paracentesis plus fluid replacement

Reference

Aldosterone antagonists plus loop diuretics
(1 RCT; 31 participants)

Rate ratio 4.12
(0.87 to 34.02)
Network estimate

118 per 1000

485 per 1000
(103 to 4003)

367 more per 1000
(15 fewer to 3885 more)

Very low1,2,3

Paracentesis plus systemic vasoconstrictors
(1 RCT; 25 participants)

Rate ratio 1.37
(0.36 to 5.82)
Network estimate

118 per 1000

161 per 1000
(42 to 685)

43 more per 1000
(76 fewer to 567 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors
(No direct RCT)

Rate ratio 3.30
(0.38 to 38.51)
Network estimate

118 per 1000

388 per 1000
(45 to 4531)

271 more per 1000
(73 fewer to 4413 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus systemic vasodilator
(No direct RCT)

Rate ratio 4.25
(0.53 to 46.99)
Network estimate

118 per 1000

501 per 1000
(62 to 5529)

383 more per 1000
(55 fewer to 5411 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus systemic vasodilator
(No direct RCT)

Rate ratio 2.41
(0.24 to 29.67)
Network estimate

118 per 1000

284 per 1000
(28 to 3490)

166 more per 1000
(89 fewer to 3372 more)

Very low1,2,3

Liver transplantation at maximal follow‐up
Total studies: 11
Total participants: 596

Paracentesis plus fluid replacement

Reference

Paracentesis plus systemic vasoconstrictors
(4 RCTs; 145 participants)

HR 1.08
(0.11 to 10.35)
Network estimate

121 per 1000

131 per 1000
(14 to 1000)

10 more per 1000
(108 fewer to 879 more)

Very low1,2,3

Transjugular intrahepatic portosystemic shunt
(6 RCTs; 427 participants)

HR 0.87
(0.52 to 1.44)
Network estimate

121 per 1000

106 per 1000
(63 to 175)

15 fewer per 1000
(58 fewer to 54 more)

Very low1,2,3

Paracentesis plus reinfusion
(1 RCT; 24 participants)

HR 2.56
(0.20 to 90.92)
Network estimate

121 per 1000

310 per 1000
(25 to 1000)

189 more per 1000
(97 fewer to 879 more)

Very low1,2,3

Symptomatic resolution of ascites at maximal follow‐up

None of the trials reported this outcome

Resolution of ascites at maximal follow‐up (by ultrasound)
Total studies: 17
Total participants: 1007

Paracentesis plus fluid replacement

Reference

Aldosterone antagonists plus loop diuretics
(3 RCTs; 125 participants)

HR 1.10
(0.12 to 10.74)
Network estimate

158 per 1000

174 per 1000
(18 to 1000)

16 more per 1000
(140 fewer to 842 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement
(No direct RCT)

HR 1.17
(0.01 to 98.79)
Network estimate

158 per 1000

185 per 1000
(2 to 1000)

27 more per 1000
(156 fewer to 842 more)

Very low1,2,3,4

Transjugular intrahepatic portosystemic shunt
(6 RCTs; 392 participants)

HR 9.44
(1.93 to 62.68)
Network estimate

158 per 1000

1000 per 1000
(305 to 1000)

842 more per 1000
(147 more to 842 more)

Very low1,2,4

No active treatment
(No direct RCT)

HR 0.16
(0.00 to 17.37)
Network estimate

158 per 1000

26 per 1000
(0 to 1000)

132 fewer per 1000
(158 fewer to 842 more)

Very low1,2,3,4

Loop diuretics
(No direct RCT)

HR 2.26
(0.01 to 846.41)
Network estimate

158 per 1000

357 per 1000
(1 to 1000)

199 more per 1000
(157 fewer to 842 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus albumin
(No direct RCT)

HR 3.28
(0.09 to 118.39)
Network estimate

158 per 1000

517 per 1000
(15 to 1000)

360 more per 1000
(143 fewer to 842 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors
(No direct RCT)

HR 8.81
(0.06 to 1908.36)
Network estimate

158 per 1000

1000 per 1000
(10 to 1000)

842 more per 1000
(148 fewer to 842 more)

Very low1,2,3,4

Aldosterone antagonists plus paracentesis plus fluid replacement
(1 RCT; 36 participants)

HR 30.63
(5.06 to 692.98)
Direct estimate

158 per 1000

1000 per 1000
(799 to 1000)

842 more per 1000
(641 more to 842 more)

Low1,2

Other features of decompensation at maximal follow‐up
Total studies: 25
Total participants: 1756

Paracentesis plus fluid replacement

Reference

Aldosterone antagonists plus loop diuretics
(4 RCTs; 242 participants)

Rate ratio 2.04
(1.37 to 3.10)
Network estimate

439 per 1000

896 per 1000
(602 to 1360)

458 more per 1000
(164 more to 922 more)

Very low1,2,4

Paracentesis plus systemic vasoconstrictors
(3 RCTs; 114 participants)

Rate ratio 0.76
(0.14 to 3.61)
Network estimate

439 per 1000

332 per 1000
(62 to 1582)

107 fewer per 1000
(377 fewer to 1144 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement
(No direct RCT)

Rate ratio 1.04
(0.56 to 1.93)
Network estimate

439 per 1000

455 per 1000
(244 to 848)

16 more per 1000
(195 fewer to 409 more)

Very low1,2,3,4

Transjugular intrahepatic portosystemic shunt
(7 RCTs; 452 participants)

Rate ratio 1.17
(0.92 to 1.49)
Network estimate

439 per 1000

515 per 1000
(405 to 655)

76 more per 1000
(33 fewer to 217 more)

Very low1,2,3,4

No active treatment
(No direct RCT)

Rate ratio 3.34
(0.85 to 13.94)
Network estimate

439 per 1000

1466 per 1000
(374 to 6115)

1028 more per 1000
(64 fewer to 5677 more)

Very low1,2,3,4

Loop diuretics
(No direct RCT)

Rate ratio 0.95
(0.40 to 2.23)
Network estimate

439 per 1000

418 per 1000
(176 to 977)

21 fewer per 1000
(262 fewer to 538 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus albumin
(No direct RCT)

Rate ratio 1.56
(0.84 to 2.87)
Network estimate

439 per 1000

682 per 1000
(369 to 1260)

244 more per 1000
(69 fewer to 821 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus peritoneovenous shunt
(No direct RCT)

Rate ratio 0.84
(0.41 to 1.70)
Network estimate

439 per 1000

369 per 1000
(180 to 747)

70 fewer per 1000
(258 fewer to 308 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors
(No direct RCT)

Rate ratio 0.53
(0.02 to 4.98)
Network estimate

439 per 1000

233 per 1000
(7 to 2185)

205 fewer per 1000
(431 fewer to 1747 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus systemic vasodilator
(No direct RCT)

Rate ratio 0.53
(0.02 to 4.99)
Network estimate

439 per 1000

233 per 1000
(8 to 2190)

206 fewer per 1000
(431 fewer to 1751 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus systemic vasodilator
(No direct RCT)

Rate ratio 0.53
(0.02 to 5.11)
Network estimate

439 per 1000

231 per 1000
(7 to 2241)

208 fewer per 1000
(431 fewer to 1802 more)

Very low1,2,3,4

Systemic vasoconstrictors plus albumin
(No direct RCT)

Rate ratio 3.90
(0.96 to 16.98)
Network estimate

439 per 1000

1712 per 1000
(422 to 7447)

1274 more per 1000
(16 fewer to 7009 more)

Very low1,2,3,4

*Anticipated absolute effect. Anticipated absolute effect compares two risks by calculating the difference between the risks of the intervention group with the weighted median risk of the control group.
**Ranking is not provided because of the considerable uncertainty in the ranking.
CrI: Credible interval; OR: Odds Ratio; HR: Hazard Ratio.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

1Downgraded one level for risk of bias because the trial(s) included in the analysis was/were at high risk of bias
2Downgraded one level for imprecision because the sample size was small
3Downgraded one level for imprecision because the credible intervals were wide (includes clinical benefit and harms)
4Downgraded one level for inconsistency because there was evidence of statistical heterogeneity

Antecedentes

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Descripción de la afección

Cirrosis hepática

El hígado es un órgano complejo con múltiples funciones, incluyendo el metabolismo de los carbohidratos, el metabolismo de las grasas, el metabolismo de las proteínas, el metabolismo de los medicamentos, las funciones sintéticas, las funciones de almacenamiento, las funciones digestivas, las funciones excretoras y las funciones inmunológicas (Read 1972). La cirrosis hepática es una enfermedad hepática en la que la microcirculación normal, la anatomía vascular macroscópica y la arquitectura hepática se han destruido y alterado de forma variable con tabiques fibrosos que rodean a los nódulos parenquimatosos regenerados o en proceso de regeneración (Tsochatzis 2014; NCBI 2018a). Las principales causas de la cirrosis hepática incluyen el consumo excesivo de alcohol, la hepatitis viral, la enfermedad hepática grasa no relacionada con el alcohol, la enfermedad hepática autoinmune y la enfermedad hepática metabólica (Williams 2014; Ratib 2015; Setiawan 2016). La prevalencia global de la cirrosis hepática es difícil de determinar, ya que la mayoría de las estimaciones corresponden a la enfermedad hepática crónica (que incluye la fibrosis hepática y la cirrosis hepática). En estudios realizados en los Estados Unidos, la prevalencia de la enfermedad hepática crónica varía entre el 0,3% y el 2,1% (Scaglione 2015; Setiawan 2016); en el Reino Unido, la prevalencia fue del 0,1% en un estudio (Fleming 2008). En 2010, la cirrosis hepática fue responsable de un estimado del 2% de todas las muertes en el mundo, equivalente a un millón de muertes (Mokdad 2014). Existe una tendencia creciente de muertes relacionadas con la cirrosis en algunos países como el Reino Unido, mientras que hay una tendencia decreciente en otros países como Francia (Mokdad 2014; Williams 2014). La causa principal de complicaciones y muertes en pacientes con cirrosis hepática se debe al desarrollo de hipertensión portal clínicamente significativa (gradiente de presión venosa hepática de al menos 10 mmHg) (De Franchis 2015). Algunas de las características clínicas de la descompensación incluyen ictericia, coagulopatía, ascitis, hemorragia de las várices, encefalopatía hepática e insuficiencia renal (De Franchis 2015; McPherson 2016; EASL 2018). La cirrosis descompensada es la indicación más frecuente para el trasplante de hígado (Merion 2010; Adam 2012).

Ascitis

La ascitis es la acumulación libre de líquidos en el abdomen (cavidad peritoneal) (NCBI 2018b), y es una característica de descompensación hepática (Tsochatzis 2017). Aproximadamente el 20% de los pacientes con cirrosis presentan ascitis (D'Amico 2014). Aproximadamente del 1% al 4% de los pacientes con cirrosis desarrollan ascitis cada año (D'Amico 2006; D'Amico 2014). La ascitis es el primer signo de descompensación hepática en aproximadamente un tercio de los pacientes con cirrosis hepática compensada (D'Amico 2014). Las ascitis se puede clasificar como ascitis grado 1, que es una ascitis leve que sólo se puede detectar mediante un examen de ultrasonido; ascitis grado 2 o moderada que se manifiesta por una distensión simétrica moderada del abdomen; y ascitis grado 3 que es una ascitis grande o gruesa con una marcada distensión abdominal (Arroyo 1996; Moore 2003). A la ascitis grado 3 también se le llama ascitis "tensa" (Arroyo 1996). La ascitis que no responde al tratamiento médico se denomina ascitis "refractaria" (Arroyo 1996; Moore 2003). En la tabla 1 figuran criterios detallados para la definición de la ascitis refractaria (Moore 2003).

En los pacientes con cirrosis, la aparición de la ascitis y el tratamiento de la misma provocan una disminución de la calidad de vida relacionada con la salud (Kim 2006; Les 2010; Orr 2014). La resolución de la ascitis puede dar lugar a una mejoría de la calidad de vida relacionada con la salud en los pacientes con ascitis (Orr 2014). La mortalidad al año en los pacientes con cirrosis hepática y ascitis es del 20%, que aumenta al 57% en los pacientes con ascitis y hemorragia de las várices (D'Amico 2006). El tratamiento de la ascitis y sus complicaciones requiere importantes recursos. Un estudio informó que los pacientes con cirrosis hepática y ascitis requerían como promedio un ingreso hospitalario por mes y una estancia de diez días en el hospital por mes (Fagan 2014).

Fisiopatología de la ascitis

Se desconoce el mecanismo exacto por el cual se desarrolla la ascitis en los pacientes con cirrosis hepática. La hipertensión portal causa vasodilatación arterial de la circulación esplácnica (dilatación de los vasos sanguíneos que irrigan los órganos digestivos del abdomen como el hígado, el páncreas y el intestino) (Ginès 2009; Moore 2013). Esta activa el sistema renina‐angiotensina (Ginès 2009; Moore 2013) y conduce a la retención de líquidos (Moore 2013). Además, la permeabilidad de la pared de los vasos aumenta debido al incremento patológico del factor de crecimiento del endotelio vascular (VEGF) (Colle 2008), y la presión oncótica disminuye debido a la disminución de la síntesis de la albúmina por el hígado enfermo, lo que provoca fugas en los vasos sanguíneos esplácnicos en los pacientes con hipertensión portal (Moore 2013). Lo anterior provoca la acumulación de líquidos en la cavidad peritoneal, es decir, la ascitis (Moore 2013).

Descripción de la intervención

Aunque los pacientes con cirrosis y ascitis grado 2, ascitis grado 3 y ascitis refractaria se deben considerar para trasplante de hígado (EASL 2010; Runyon 2013; EASL 2016; EASL 2018), la ascitis cirrótica sola sin otras características de enfermedad hepática avanzada, como ictericia, hemorragia de las várices, peritonitis bacteriana espontánea o síndrome hepatorrenal, por lo general se trata con métodos menos invasivos que el trasplante de hígado (EASL 2010). Según las guías de la European Association for the Study of the Liver (EASL) y la American Association for the Study of Liver Diseases (AASLD), la ascitis grado 1 no requiere un tratamiento específico; la grado 2 requiere una dieta con restricción de sal y diuréticos; y la grado 3 requiere una paracentesis de gran volumen (extracción de varios litros de líquido ascítico) junto con una dieta con restricción de sal y diuréticos (EASL 2010; Runyon 2013; EASL 2018).

En los pacientes con ascitis refractaria a los diuréticos, la paracentesis y la derivación portosistémica intrahepática transyugular (TIPS, por sus siglas en inglés) son los principales tratamientos según las guías de la EASL y la AASLD (EASL 2010; Runyon 2013; EASL 2018). Además, las guías de la AASLD indican que la midodrina (un vasoconstrictor) se debe considerar en los pacientes con ascitis refractaria (Runyon 2013), mientras que no es recomendado por las guías de la EASL (EASL 2018).

No está clara la función de los vasoconstrictores, la ultrafiltración y reinfusión espontáneas (filtrar el líquido ascítico extraído y reinfundir las proteínas) ni la bomba de bajo flujo para eliminar el líquido de la ascitis (desvía automáticamente el líquido ascítico a la vejiga urinaria, desde donde se excreta en la orina) en el tratamiento de los pacientes con ascitis y las guías de la EASL y la AASLD no recomiendan su uso habitual (EASL 2010; Runyon 2013). En la actualidad las derivaciones portosistémicas quirúrgicas sólo se recomiendan en pacientes con ascitis refractaria no apta para TIPS, paracentesis repetida o trasplante de hígado (Runyon 2013).

De qué manera podría funcionar la intervención

Los diuréticos aumentan la excreción de líquidos, disminuyendo así la acumulación de éstos: la acumulación de líquidos es uno de los mecanismos de desarrollo de la ascitis y la disminución de la acumulación de líquidos puede llevar a la resolución de la ascitis. Los fármacos vasoconstrictores sistémicos disminuyen la vasodilatación esplácnica, que es otro mecanismo de desarrollo de la ascitis.

La paracentesis implica la extracción del líquido ascítico. Es poco probable que la extracción de hasta cinco litros de líquido en una sesión de paracentesis cause un shock circulatorio (EASL 2010; Runyon 2013), pero la extracción de más de este volumen puede provocarlo. Varios métodos utilizados para tratar de afrontar este problema son la administración de albúmina, coloides como el hidroxietilalmidón, vasoconstrictores como la midodrina o la reinfusión de las proteínas del líquido ascítico en la circulación sistémica (Bruno 1992; Altman 1998; Appenrodt 2008). Sin embargo, los efectos beneficiosos de los expansores de plasma en los pacientes con cirrosis y grandes ascitis tratados con paracentesis abdominal son cuestionables (Simonetti 2019).

Los procedimientos de TIPS y otras formas quirúrgicas de derivación portosistémica tienen como objetivo disminuir la presión venosa portal, la principal causa de ascitis en los pacientes con cirrosis hepática.

Por qué es importante realizar esta revisión

Es importante proporcionar un tratamiento óptimo a los pacientes con ascitis para mejorar la supervivencia y la calidad de vida relacionada con la salud. Existen varios tratamientos diferentes; sin embargo, se desconoce la eficacia relativa y la combinación óptima. Al comienzo de este proyecto se disponía de una revisión Cochrane sobre TIPS versus paracentesis en pacientes con cirrosis con ascitis refractaria (Saab 2006); sin embargo, hasta la fecha, no se han realizado metanálisis en red sobre el tema. El metanálisis en red permite combinar la evidencia directa e indirecta y la calificación de diferentes intervenciones para diferentes resultados (Salanti 2011; Salanti 2012). Con esta revisión sistemática y este metanálisis en red se proporciona el mejor nivel de evidencia de los efectos beneficiosos y perjudiciales de los diferentes tratamientos para la ascitis en pacientes con cirrosis hepática descompensada. También se han presentado los resultados de las comparaciones directas siempre que ha sido posible, además de realizar el metanálisis en red.

Objetivos

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Comparar los efectos beneficiosos y perjudiciales de los diferentes tratamientos para la ascitis en pacientes con cirrosis hepática descompensada mediante un metanálisis en red y generar clasificaciones de los diferentes tratamientos para la ascitis según su seguridad y eficacia.

Métodos

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Criterios de inclusión de estudios para esta revisión

Tipos de estudios

Para este metanálisis en red se consideraron sólo los ensayos clínicos aleatorizados (incluidos los ensayos clínicos aleatorizados cruzados y grupales), independientemente del idioma, el estado de publicación o la fecha de publicación. Se excluyeron los estudios de otros diseños debido al riesgo de sesgo en dichos estudios. La inclusión de evidencia observacional indirecta podría debilitar el metanálisis en red, pero también se podría considerar una fortaleza para evaluar eventos adversos poco frecuentes. Está bien establecido que la exclusión de los estudios no aleatorizados aumenta la atención en los efectos beneficiosos potenciales y reduce la atención en los riesgos de eventos adversos graves y de cualquier evento adverso. Sin embargo, estos estudios no se incluyeron debido a los hallazgos de esta revisión, es decir, existe una considerable incertidumbre sobre los efectos beneficiosos de los diferentes tratamientos para la ascitis.

Tipos de participantes

Se incluyeron ensayos clínicos aleatorizados con pacientes adultos (de 18 años o más) con cirrosis hepática descompensada sometidos a tratamiento para la ascitis. Se excluyeron los ensayos clínicos aleatorizados en los que los participantes se habían sometido previamente a un trasplante hepático.

Tipos de intervenciones

Se incluyó cualquiera de los siguientes tratamientos para comparar uno con otro, ya sea solo o combinado.

  • Diuréticos (las diferentes clases de diuréticos en función de su mecanismo de acción se tratarán como intervenciones separadas, por ejemplo, los diuréticos de asa como la furosemida, la torsemida; los antagonistas de la aldosterona como la espironolactona o el canenoato de potasio);

  • Paracentesis de gran volumen (extracción del líquido ascítico) con diferentes líquidos para prevenir la disfunción circulatoria (por ejemplo, albúmina, hidroxietilalmidón, etc.) ("paracentesis más reposición de líquidos");

  • Ultrafiltración y reinfusión espontáneas (filtrar el líquido ascítico extraído y reinfundir las proteínas);

  • Bomba de bajo flujo para eliminar el líquido de la ascitis (desvía automáticamente el líquido ascítico a la vejiga urinaria, desde donde se excreta en la orina);

  • Vasoconstrictor sistémico (por ejemplo, terlipresina, midodrina);

  • Procedimiento de TIPS (disminución de la hipertensión portal);

  • Otras formas de derivación portosistémica (disminución de la hipertensión portal);

  • Ninguna intervención activa (ninguna intervención relacionada con la ascitis o placebo).

La "paracentesis más reposición de líquidos" se consideró el grupo de referencia. Cada una de las categorías anteriores se consideró como un "nodo de tratamiento"; la única excepción fueron los diuréticos, en los que se consideraron diferentes clases de diuréticos como diferentes nodos de tratamiento. Las variaciones de los fármacos dentro de la misma clase de diuréticos, las dosis de los fármacos, la frecuencia y la duración de las intervenciones se consideraron el mismo nodo de tratamiento. Cada combinación diferente de las categorías se consideró nodos de tratamiento diferentes.

Se excluyeron los ensayos que evaluaron cointervenciones como la restricción de líquidos, la dieta restringida en sal o fármacos como los antagonistas de la vasopresina, que se utilizan como suplementos de los diuréticos para afrontar efectos adversos como la hiponatremia. Sin embargo, se incluyeron los ensayos en los que dichas cointervenciones se administraron por igual en ambos brazos del ensayo.

La factivilidad de la suposición de transitividad del metanálisis en red se evaluó mediante el análisis de los criterios de inclusión y exclusión en los estudios. La suposición de transitividad es la suposición de que los participantes incluidos en los diferentes ensayos con diferentes tratamientos para el síndrome hepatorrenal se pueden considerar parte de un ensayo clínico aleatorizado de brazos múltiples y se podrían haber asignado al azar a cualquiera de las intervenciones (Salanti 2012). En otras palabras, cualquier participante que cumpla los criterios de inclusión tiene, en principio, la misma probabilidad de ser asignado al azar a cualquiera de las intervenciones elegibles mencionadas anteriormente. Para ello es necesario que la información sobre los posibles modificadores de los efectos, como el grado de ascitis (ascitis grado 2, ascitis grado 3 o ascitis refractaria) sea la misma en todos los ensayos. Cuando fue posible se realizó un metanálisis separado para cada uno de los diferentes tipos de ascitis, para asegurar que se redujeran las preocupaciones sobre la suposición de transitividad.

Tipos de medida de resultado

Resultados primarios

  • Mortalidad por todas las causas en el seguimiento máximo, es decir, el resultado medido en la última ocasión en que se hizo un seguimiento del participante (tiempo transcurrido hasta la muerte).

  • Calidad de vida relacionada con la salud utilizando una escala validada como la EQ‐5D o la encuesta de salud de 36 ítems (SF‐36) en el seguimiento máximo (EuroQol 2018; Optum 2018).

  • Eventos adversos graves (durante la intervención o en el transcurso de los seis meses posteriores a su cese). Un evento adverso grave se definió como cualquier evento que pudiera aumentar la mortalidad; fuera potencialmente mortal; requiriera hospitalización; resultara en una discapacidad persistente o significativa; fuera una anomalía congénita o un defecto congénito; o cualquier evento médico importante que pudiera poner en peligro al paciente o requerir intervención para prevenirlo (ICH‐GCP 1997). Sin embargo, ninguno de los autores de los ensayos definieron los eventos adversos graves. Por lo tanto, se utilizó la lista proporcionada por los autores de los ensayos para los eventos adversos graves (como se indica en el protocolo).

    • proporción de pacientes con uno o más eventos adversos graves;

    • número de eventos adversos graves por participante.

Resultados secundarios

  • Cualquier evento adverso (durante la intervención o en el transcurso de los seis meses posteriores a su cese): un evento adverso se definió como cualquier acontecimiento médico desfavorable que no guarde necesariamente una relación causal con la intervención, pero que dé lugar a una reducción de la dosis o a la interrupción de la intervención (en cualquier momento después del inicio de la intervención) (ICH‐GCP 1997). Sin embargo, ninguno de los autores de la revisión definió el "evento adverso". Por lo tanto, se utilizaron las listas proporcionadas por los autores de los ensayos para los eventos adversos (como se indica en el protocolo de la revisión).

    • proporción de pacientes con uno o más eventos adversos;

    • número de eventos adversos por participante.

  • Tiempo hasta el trasplante hepático (seguimiento máximo).

  • Tiempo de resolución de la ascitis (como quiera que se haya definido por los autores en el seguimiento máximo):

    • recuperación sintomática;

    • resolución según el ultrasonido.

  • Número de episodios de descompensación (seguimiento máximo).

Resultados exploratorios

  • Duración de la estancia hospitalaria (todos los ingresos hospitalarios hasta el seguimiento máximo).

  • Número de días de ausencia al trabajo (en pacientes que trabajan) (seguimiento máximo).

  • Costes del tratamiento (incluye el coste del tratamiento y cualquier complicación resultante).

Los resultados se seleccionaron sobre la base de su importancia para los pacientes en una encuesta relacionada con las prioridades de investigación para los pacientes con enfermedades hepáticas (Gurusamy 2019) y sobre la base de la retroalimentación del paciente y del representante público de este proyecto, así como de una encuesta en línea sobre los resultados promovida a través de la Red Cochrane de Consumidores (Cochrane Consumer Network).

Métodos de búsqueda para la identificación de los estudios

Búsquedas electrónicas

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE Ovid, Embase Ovid, and Science Citation Index Expanded (Web of Science) from inception to date of search for randomised clinical trials comparing two or more of the above interventions without applying any language restrictions (Royle 2003). We searched for all possible comparisons formed by the interventions of interest. To identify further ongoing or completed trials, we also searched clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch/) which searches various trial registers, including ISRCTN and ClinicalTrials.gov. We also searched the European Medical Agency (EMA) (www.ema.europa.eu/ema/) and USA Food and Drug Administration (FDA) (www.fda.gov) registries for randomised clinical trials. We provided the search strategies along with the date of search in Appendix 1.

Búsqueda de otros recursos

We searched the references of the identified trials and the existing Cochrane Reviews on ascites in liver cirrhosis to identify additional trials for inclusion.

Obtención y análisis de los datos

Selección de los estudios

Two review authors (KG and AB, DR, LP, or MP) independently identified trials for inclusion by screening the titles and abstracts of articles identified by the literature search, and sought full‐text articles of any references identified by at least one review author for potential inclusion. We selected trials for inclusion based on the full‐text articles. We listed the references that we excluded and the reasons for their exclusion in the Characteristics of excluded studies table. We also listed any ongoing trials identified primarily through the search of the clinical trial registers for further follow‐up. We resolved any discrepancies through discussion. We illustrated the study selection process in a PRISMA diagram.

Extracción y manejo de los datos

Two review authors (KG and AB, DR, LP, or MP) independently extracted the following data onto a pre‐piloted Microsoft Excel‐based data extraction form (after translation of non‐English articles).

  • Outcome data (for each outcome and for each intervention group, whenever applicable):

    • number of participants randomised;

    • number of participants included for the analysis;

    • number of participants with events for binary outcomes, mean and standard deviation for continuous outcomes, number of events and the mean follow‐up period for count outcomes, and number of participants with events and the mean follow‐up period for time‐to‐event outcomes;

    • natural logarithm of the hazard ratio and its standard error if this was reported rather than the number of participants with events and the mean follow‐up period for time‐to‐event outcomes;

    • definition of outcomes or scale used, if appropriate.

  • Data on potential effect modifiers:

    • participant characteristics such as age, sex, grade of ascites, whether refractory or recurrent ascites, the aetiology for cirrhosis, and the interval between diagnosis of ascites and treatment;

    • details of the intervention and control (including dose, frequency, and duration);

    • length of follow‐up;

    • information related to 'Risk of bias' assessment (please see below).

  • Other data:

    • year and language of publication;

    • country in which the participants were recruited;

    • year(s) in which the trial was conducted;

    • inclusion and exclusion criteria.

We collected outcomes at maximum follow‐up, but also at short‐term (up to three months) and medium‐term (from three months to five years) if this was available.

We attempted to contact the trial authors in the case of unclear or missing information. We resolved any differences in opinion through discussion.

Evaluación del riesgo de sesgo de los estudios incluidos

We followed the guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to assess the risk of bias in the included trials. Specifically, we assessed sources of bias as defined below (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Savović 2012a; Savović 2012b; Savović 2018).

Allocation sequence generation

  • 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 were adequate if performed by an independent person not otherwise involved in the trial.

  • Unclear risk of bias: the method of sequence generation was not specified.

  • High risk of bias: the sequence generation method was not random or only quasi‐randomised. We excluded such quasi‐randomised studies.

Allocation concealment

  • Low risk of bias: the allocation sequence was described as unknown to the investigators. Hence, the participants' allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomisation unit, an onsite locked computer, identical‐looking numbered sealed opaque envelopes, drug bottles or containers prepared by an independent pharmacist, or an independent investigator.

  • Unclear risk of bias: it was unclear if the allocation was hidden or if the block size was relatively small and fixed so that intervention allocations may have been foreseen in advance of, or during, enrolment.

  • High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants. We excluded such quasi‐randomised studies.

Blinding of participants and personnel

  • Low risk of bias: blinding of participants and key study personnel ensured, and it was unlikely that the blinding could have been broken; or rarely no blinding or incomplete blinding, but the review authors judged that the outcome was not likely to be influenced by lack of blinding.

  • 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.

  • High risk of bias: any of the following: no blinding or incomplete blinding, and the outcome was 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 was likely to be influenced by lack of blinding.

Blinded outcome assessment

  • Low risk of bias: blinding of outcome assessment ensured, and unlikely that the blinding could have been broken; or rarely no blinding of outcome assessment, but the review authors judged that the outcome measurement was not likely to be influenced by lack of blinding.

  • 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.

  • High risk of bias: any of the following: no blinding of outcome assessment, and the outcome measurement was 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 was likely to be influenced by lack of blinding.

Incomplete outcome data

  • 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.

  • 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.

  • High risk of bias: the results were likely to be biased due to missing data.

Selective outcome reporting

  • Low risk of bias: the trial reported the following predefined outcomes: all‐cause mortality, adverse events, and time to resolution of ascites. If the original trial protocol was available, the outcomes should have been those called for in that protocol. If we obtained the trial protocol from a trial registry (e.g. 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 that the trial was begun. If the trial protocol was registered after the trial was begun, we did not consider those outcomes to be reliable.

  • Unclear risk of bias: not all predefined, or clinically relevant and reasonably expected, outcomes were reported fully, or it was unclear whether data on these outcomes were recorded or not.

  • High risk of bias: one or more predefined or clinically relevant and reasonably expected outcomes were not reported, despite the fact that data on these outcomes should have been available and even recorded.

Other bias

  • Low risk of bias: the trial appeared to be free of other components that could put it at risk of bias (e.g. inappropriate control or dose or administration of control, baseline differences, early stopping).

  • Uncertain risk of bias: the trial may or may not have been free of other components that could put it at risk of bias.

  • High risk of bias: there were other factors in the trial that could put it at risk of bias (e.g. baseline differences, early stopping).

We considered a trial to be at low risk of bias if we assessed the trial to be at low risk of bias across all listed bias risk domains. Otherwise, we considered trials to be at high risk of bias. At the outcome level, we classified an outcome to be at low risk of bias if the allocation sequence generation, allocation concealment, blinding of participants, healthcare professionals, and outcome assessors, incomplete outcome data, and selective outcome reporting (at the outcome level) were at low risk of bias for objective and subjective outcomes (Savović 2018).

Medidas del efecto del tratamiento

Relative treatment effects

For dichotomous variables (e.g. proportion of participants with serious adverse events or any adverse events), we calculated the odds ratio (OR) with 95% credible interval (CrI) (or Bayesian confidence interval) (Severini 1993). For continuous variables (e.g. health‐related quality of life reported on the same scale), we calculated the mean difference (MD) with 95% Crl. We planned to use standardised mean difference (SMD) values with 95% Crl for health‐related quality of life if included trials used different scales. If we calculated the SMD, we planned to convert it to a common scale, for example, EQ‐5D or SF‐36 (using the standard deviation of the common scale) for the purpose of interpretation. For count outcomes (e.g. number of serious adverse events or number of any adverse events), we calculated the rate ratio (RaR) with 95% Crl. This assumes that the events are independent of each other, i.e. if a person has had an event, they are not at an increased risk of further outcomes, which is the assumption in Poisson likelihood. For time‐to‐event data (e.g. all‐cause mortality at maximal follow‐up), we calculated hazard ratios (HRs) with 95% Crl.

Relative ranking

We estimated the ranking probabilities for all interventions of being at each possible rank for each intervention for each outcome when NMA (network meta‐analysis) was performed. We obtained the surface under the cumulative ranking curve (SUCRA) (cumulative probability), rankogram, and relative ranking table with CrI for the ranking probabilities for each outcome when NMA was performed (Salanti 2011; Chaimani 2013).

Cuestiones relativas a la unidad de análisis

The unit of analysis was the participant undergoing treatment for ascites according to the intervention group to which the participant was randomly assigned.

Cluster‐randomised clinical trials

If we identified any cluster‐randomised clinical trials, we planned to include cluster‐randomised clinical trials, provided that the effect estimate adjusted for cluster correlation was available or if there was sufficient information available to calculate the design effect (which would allow us to take clustering into account). We also planned to assess additional domains of risk of bias for cluster‐randomised trials according to guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Cross‐over randomised clinical trials

If we identified any cross‐over randomised clinical trials, we planned to include only the outcomes after the period of the first intervention because the included treatments could have residual effects.

Trials with multiple intervention groups

We collected data for all trial intervention groups that met the inclusion criteria. The codes that we used for analysis accounted for the correlation between the effect sizes from studies with more than two groups.

Manejo de los datos faltantes

We performed an intention‐to‐treat analysis, whenever possible (Newell 1992); otherwise, we used the data available to us. When intention‐to‐treat analysis was not used and the data were not missing at random (for example, treatment was withdrawn due to adverse events or duration of treatment was shortened because of lack of response and such participants were excluded from analysis), this could lead to biased results; therefore, we conducted best‐worst case scenario analysis (assuming a good outcome in the intervention group and bad outcome in the control group) and worst‐best case scenario analysis (assuming a bad outcome in the intervention group and good outcome in the control group) as sensitivity analyses, whenever possible, for binary and time‐to‐event outcomes, where binomial likelihood was used.

For continuous outcomes, we imputed the standard deviation from P values, according to guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If the data were likely to be normally distributed, we used the median for meta‐analysis when the mean was not available; otherwise, we planned to simply provide a median and interquartile range of the difference in medians. If it was not possible to calculate the standard deviation from the P value or the confidence intervals, we planned to impute the standard deviation using the largest standard deviation in other trials for that outcome. This form of imputation can decrease the weight of the study for calculation of mean differences and may bias the effect estimate to no effect for calculation of standardised mean differences (Higgins 2011).

Evaluación de la heterogeneidad

We assessed clinical and methodological heterogeneity by carefully examining the characteristics and design of included trials. We also planned to assess the presence of clinical heterogeneity by comparing effect estimates (please see Subgroup analysis and investigation of heterogeneity) in trial reports of different drug dosages, different grades of ascites (grade 2 or grade 3), refractory or recurrent ascites, different aetiologies for cirrhosis (for example, alcohol‐related liver disease, viral liver diseases, autoimmune liver disease), and based on the co‐interventions (for example, both groups receive prophylactic antibiotics to decrease the risk of subacute bacterial peritonitis). Different study designs and risk of bias can contribute to methodological heterogeneity.

We assessed statistical heterogeneity by comparing the results of the fixed‐effect model meta‐analysis and the random‐effects model meta‐analysis, between‐study standard deviation (tau2 and comparing this with values reported in a study of the distribution of between‐study heterogeneity estimates) (Turner 2012), and by calculating the NMA‐specific I2 statistic (Jackson 2014) using Stata/SE 15.1. When possible, we explored substantial clinical, methodological, or statistical heterogeneity and addressed the heterogeneity in subgroup analysis (see 'Subgroup analysis and investigation of heterogeneity').

Assessment of transitivity across treatment comparisons

We assessed the transitivity assumption by comparing the distribution of the potential effect modifiers (clinical: grade of ascites (grade 2 versus grade 3) and whether refractory or recurrent ascites; and methodological: risk of bias, year of randomisation, duration of follow‐up) across the different pairwise comparisons.

Evaluación de los sesgos de notificación

For the network meta‐analysis, we planned to perform a comparison‐adjusted funnel plot. However, to interpret a comparison‐adjusted funnel plot, it is necessary to rank the studies in a meaningful way as asymmetry may be due to small sample sizes in newer studies (comparing newer treatments with older treatments) or higher risk of bias in older studies (Chaimani 2012). As there was no meaningful way in which to rank these studies (i.e. there was no specific change in the risk of bias in the studies, sample size, or the control group used over time), we judged the reporting bias by the completeness of the search (Chaimani 2012). We also considered lack of reporting of outcomes as a form of reporting bias.

Síntesis de los datos

Methods for indirect and mixed comparisons

We conducted network meta‐analyses to compare multiple interventions simultaneously for each of the primary and secondary outcomes. When two or more interventions were combined, we considered this as a separate intervention ('node'). Network meta‐analysis combines direct evidence within trials and indirect evidence across trials (Mills 2012). We obtained a network plot to ensure that the trials were connected by interventions using Stata/SE 15.1 (Chaimani 2013). We excluded any trials that were not connected to the network from the network meta‐analysis, and we reported only the direct pairwise meta‐analysis for such comparisons. We summarised the population and methodological characteristics of the trials included in the network meta‐analysis in a table based on pairwise comparisons. We conducted a Bayesian network meta‐analysis using the Markov chain Monte Carlo method in OpenBUGS 3.2.3, according to guidance from the National Institute for Health and Care Excellence (NICE) Decision Support Unit (DSU) documents (Dias 2016). We modelled the treatment contrast (i.e. log odds ratio for binary outcomes, mean difference or standardised mean difference for continuous outcomes, log rate ratio for count outcomes, and log hazard ratio for time‐to‐event outcomes) for any two interventions ('functional parameters') as a function of comparisons between each individual intervention and the reference group ('basic parameters') using appropriate likelihood functions and links (Lu 2006). We used binomial likelihood and logit link for binary outcomes, Poisson likelihood and log link for count outcomes, binomial likelihood and complementary log‐log link (a semiparametric model which excludes censored individuals from the denominator of ‘at risk’ individuals at the point when they are censored) for time‐to‐event outcomes, and normal likelihood and identity link for continuous outcomes. We used 'paracentesis plus fluid replacement' as the reference group across the networks, as this was the commonest intervention compared in the trials. We performed a fixed‐effect model and random‐effects model for the network meta‐analysis. We reported both models for comparison with the reference group in a forest plot when the results were different between the models. For each pairwise comparison in a table, we reported the fixed‐effect model if the two models reported similar results; otherwise, we reported the more conservative model, i.e. usually using the random‐effects model in the absence of ‘small‐study’ bias.

We used a hierarchical Bayesian model using three different sets of initial values to start the simulation‐based parameter estimation to assist with the assessment of convergence, employing codes provided by NICE DSU (Dias 2016). We used a normal distribution with large variance (10,000) for treatment effect priors (vague or flat priors) centred at no effect. For the random‐effects model, we used a prior distributed uniformly (limits: 0 to 5) for the between‐trial standard deviation parameter and assumed this variability would be the same across treatment comparisons (Dias 2016). We used a 'burn‐in' of 30,000 simulations, checked for convergence (of effect estimates and between‐study heterogeneity) visually (i.e. whether the values in different chains mixed very well by visualisation), and ran the models for another 10,000 simulations to obtain effect estimates. If we did not obtain convergence, we increased the number of simulations for the 'burn‐in' and used the 'thin' and 'over relax' functions to decrease the autocorrelation. If we still did not obtain convergence, we used alternate initial values and priors employing methods suggested by Van Valkenhoef 2012. We estimated the probability that each intervention ranked at each of the possible positions using the NICE DSU codes (Dias 2016).

Assessment of inconsistency

We assessed inconsistency (statistical evidence of the violation of the transitivity assumption) by fitting both an inconsistency model and a consistency model. We used inconsistency models employed in the NICE DSU manual, as we used a common between‐study standard deviation (Dias 2014). In addition, we used design‐by‐treatment full interaction model and inconsistency factor (IF) plots to assess inconsistency (Higgins 2012; Chaimani 2013), when applicable. We used Stata/SE 15.1 to create IF plots. In the presence of inconsistency, we assessed whether the inconsistency was due to clinical or methodological heterogeneity by performing separate analyses for each of the different subgroups mentioned in the Subgroup analysis and investigation of heterogeneity or limited network meta‐analysis to a more compatible subset of trials, when possible.

Direct comparison

We performed the direct comparisons using the same codes and the same technical details.

Análisis de subgrupos e investigación de la heterogeneidad

We planned to assess the differences in the effect estimates between the following subgroups and investigated heterogeneity and inconsistency using meta‐regression with the help of the codes provided in NICE DSU guidance (Dias 2012a), if we included a sufficient number of trials (when there were at least two trials in at least two of the subgroups). We planned to use the following trial‐level covariates for meta‐regression.

  • Trials at low risk of bias (risk of bias in all domains were low) compared to trials at high risk of bias (risk of bias was unclear or high in at least one of the domains).

  • The grade of ascites (grade 2 or grade 3 or refractory/recurrent ascites).

  • The aetiology for cirrhosis (for example, alcohol‐related liver disease, viral liver diseases, autoimmune liver disease).

  • The interval between the diagnosis of ascites and the start of treatment.

  • The co‐interventions (for example, both groups received prophylactic antibiotics to decrease the risk of subacute bacterial peritonitis).

  • The period of follow‐up (short‐term: up to three months, medium‐term: more than three months to five years, long‐term: more than five years).

  • The definition used by authors for serious adverse events and any adverse event (ICH‐GCP 1997 compared to other definitions).

We calculated a single common interaction term which assumes that each relative treatment effect compared to a common comparator treatment (i.e. paracentesis plus fluid replacement) is impacted in the same way by the covariate in question, when applicable (Dias 2012a). If the 95% Crl of the interaction term did not overlap zero, we considered this statistically significant heterogeneity or inconsistency (depending upon the factor being used as covariate).

Análisis de sensibilidad

If there were post‐randomisation dropouts, we reanalysed the results using the best‐worst case scenario and worst‐best case scenario analyses as sensitivity analyses whenever possible. We also performed a sensitivity analysis excluding the trials in which mean or standard deviation, or both, were imputed, and we used the median standard deviation in the trials to impute missing standard deviations.

Presentation of results

We followed the PRISMA‐NMA statement while reporting (Hutton 2015). We presented the effect estimates with 95% CrI for each pairwise comparison calculated from the direct comparisons and network meta‐analysis. We originally planned to present the cumulative probability of the treatment ranks (i.e. the probability that the intervention was within the top two, the probability that the intervention was within the top three, etc) but we did not present these because of the sparse data which can lead to misinterpretation of results due to large uncertainty in the rankings (the CrI was 0 to 1 for all the ranks) in graphs (SUCRA) (Salanti 2011). We plotted the probability that each intervention was best, second best, third best, etc. for each of the different outcomes (rankograms), which are generally considered more informative (Salanti 2011; Dias 2012b), but we did not present these because of the sparse data which can lead to misinterpretation of results due to large uncertainty in the rankings (the CrI was 0 to 1 for all the ranks). We uploaded all the raw data and the codes used for analysis in the European Organization for Nuclear Research open source database (Zenodo): the link is: http://doi.org/10.5281/zenodo.3531818.

Grading of evidence

We presented 'Summary of findings' tables for all the primary and secondary outcomes (see Primary outcomes; Secondary outcomes). We followed the approach suggested by Yepes‐Nunez and colleagues (Yepes‐Nunez 2019). First, we calculated the direct and indirect effect estimates (when possible) and 95% Crl using the node‐splitting approach (Dias 2010), that is, calculating the direct estimate for each comparison by including only trials in which there was direct comparison of interventions and the indirect estimate for each comparison by excluding the trials in which there was direct comparison of interventions (and ensuring a connected network). Next, we rated the quality of direct and indirect effect estimates using GRADE methodology which takes into account the risk of bias, inconsistency (heterogeneity), directness of evidence (including incoherence, the term used in GRADE methodology for inconsistency in network meta‐analysis), imprecision, and publication bias (Guyatt 2011). We then presented the relative and absolute estimates of the meta‐analysis with the best certainty of evidence (Yepes‐Nunez 2019). We also presented the 'Summary of findings' tables in a second format presenting all the outcomes for selected interventions (Yepes‐Nunez 2019): we selected the four interventions (aldosterone antagonists plus loop diuretics, paracentesis plus systemic vasoconstrictors, aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement, and transjugular intrahepatic portosystemic shunt) which were compared in the most trials (Table 1).

Recommendations for future research

We provided recommendations for future research in the population, intervention, control, outcomes, period of follow‐up, and study design, based on the uncertainties that we identified from the existing research.

Results

Description of studies

Results of the search

We identified 4877 references through electronic searches of CENTRAL (n = 1095), MEDLINE Ovid (n = 2093), Embase Ovid (n = 875), Science Citation Index expanded (n = 779), ClinicalTrials.gov (n = 35), and WHO Trials register (n = 0). After removing duplicate references, there were 3890 references. We excluded 3713 clearly irrelevant references through reading titles and abstracts. We identified no additional references by reference searching and by searching the EMA and FDA. We retrieved a total of 177‐full text references for further assessment in detail. We excluded 97 references (78 studies) for the reasons stated in the Characteristics of excluded studies. There were six ongoing trials (seven references) without interim data (Characteristics of ongoing studies). Thus, we included a total of 49 trials described in 73 references (Characteristics of included studies). The reference flow is shown in Figure 2.

Figure 2
Study flow diagram.

Study flow diagram.

Included studies

Forty‐nine trials were included (Gregory 1977; Fogel 1981; Descos 1983; Gines 1987; Salerno 1987; Mchutchison 1989; Stanley 1989b; Chesta 1990; Ginès 1991; Strauss 1991; Acharya 1992; Bruno 1992; Hagege 1992; Ljubici 1994; Sola 1994; Ginès 1995; Schaub 1995; Lebrec 1996; Chang 1997; Fernandez‐Esparrach 1997; Graziotto 1997; Mehta 1998; Gentilini 1999a; Rossle 2000; Ginès 2002; Moreau 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Singh 2006a; Singh 2006b; Lata 2007; Appenrodt 2008; Singh 2008; Licata 2009; Narahara 2011; Raza 2011; Al Sebaey 2012; Amin 2012; Bari 2012; Singh 2012a; Singh 2013; Ali 2014; Hamdy 2014; Tuttolomondo 2016; Bureau 2017c; Rai 2017; Caraceni 2018; Sola 2018). A total of 3521 participants were randomised to different interventions. The number of participants within each trial ranged from 20 to 440. A total of 2870 participants from 42 trials were included in one or more outcomes (Gregory 1977; Fogel 1981; Descos 1983; Gines 1987; Salerno 1987; Chesta 1990; Ginès 1991; Strauss 1991; Acharya 1992; Hagege 1992; Ljubici 1994; Sola 1994; Ginès 1995; Schaub 1995; Lebrec 1996; Fernandez‐Esparrach 1997; Graziotto 1997; Mehta 1998; Gentilini 1999a; Rossle 2000; Ginès 2002; Moreau 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Singh 2006a; Singh 2006b; Lata 2007; Singh 2008; Licata 2009; Narahara 2011; Raza 2011; Bari 2012; Singh 2012a; Singh 2013; Ali 2014; Hamdy 2014; Tuttolomondo 2016; Bureau 2017c; Rai 2017; Caraceni 2018; Sola 2018). The mean or median age in the trials ranged from 43 to 64 years in the trials that reported this information (Gregory 1977; Fogel 1981; Descos 1983; Gines 1987; Salerno 1987; Chesta 1990; Ginès 1991; Strauss 1991; Acharya 1992; Bruno 1992; Hagege 1992; Ljubici 1994; Sola 1994; Ginès 1995; Lebrec 1996; Chang 1997; Fernandez‐Esparrach 1997; Graziotto 1997; Mehta 1998; Gentilini 1999a; Rossle 2000; Ginès 2002; Moreau 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Singh 2006a; Singh 2006b; Lata 2007; Appenrodt 2008; Singh 2008; Licata 2009; Narahara 2011; Raza 2011; Al Sebaey 2012; Bari 2012; Singh 2012a; Singh 2013; Ali 2014; Hamdy 2014; Tuttolomondo 2016; Bureau 2017c; Rai 2017; Caraceni 2018; Sola 2018). The proportion of females ranged from 0.0% to 47.6% in the trials that reported this information (Gregory 1977; Fogel 1981; Descos 1983; Gines 1987; Salerno 1987; Ginès 1991; Strauss 1991; Acharya 1992; Bruno 1992; Hagege 1992; Ljubici 1994; Sola 1994; Ginès 1995; Lebrec 1996; Chang 1997; Fernandez‐Esparrach 1997; Graziotto 1997; Mehta 1998; Gentilini 1999a; Rossle 2000; Ginès 2002; Moreau 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Singh 2006a; Singh 2006b; Lata 2007; Appenrodt 2008; Singh 2008; Licata 2009; Narahara 2011; Raza 2011; Al Sebaey 2012; Bari 2012; Singh 2012a; Singh 2013; Hamdy 2014; Tuttolomondo 2016; Bureau 2017c; Rai 2017; Caraceni 2018; Sola 2018). The follow‐up period in the trials ranged from 0.1 to 84 months in the trials that reported this information. Twenty‐eight trials had short‐term follow‐up (Gregory 1977; Fogel 1981; Descos 1983; Mchutchison 1989; Strauss 1991; Acharya 1992; Bruno 1992; Hagege 1992; Ljubici 1994; Schaub 1995; Chang 1997; Fernandez‐Esparrach 1997; Mehta 1998; Moreau 2002; Singh 2006a; Singh 2006b; Lata 2007; Appenrodt 2008; Singh 2008; Licata 2009; Raza 2011; Al Sebaey 2012; Amin 2012; Singh 2013; Ali 2014; Hamdy 2014; Tuttolomondo 2016; Rai 2017); 19 trials had medium‐term follow‐up (Gines 1987; Salerno 1987; Chesta 1990; Ginès 1991; Sola 1994; Ginès 1995; Lebrec 1996; Graziotto 1997; Gentilini 1999a; Rossle 2000; Ginès 2002; Sanyal 2003; Salerno 2004; Narahara 2011; Bari 2012; Singh 2012a; Bureau 2017c; Caraceni 2018; Sola 2018); only two trials had long‐term follow‐up (Stanley 1989b; Romanelli 2006).

Twenty‐five trials reported the proportion of participants who had ascites grade 2: in 23 trials, none of the participants had ascites grade 2; these trials included only participants with grade 3 (Descos 1983; Gines 1987; Salerno 1987; Chesta 1990; Acharya 1992; Bruno 1992; Ljubici 1994; Sola 1994; Chang 1997; Fernandez‐Esparrach 1997; Graziotto 1997; Rossle 2000; Moreau 2002; Singh 2006a; Singh 2006b; Lata 2007; Appenrodt 2008; Singh 2008; Al Sebaey 2012; Amin 2012; Ali 2014; Hamdy 2014; Bureau 2017c); in the remaining two trials, the proportion of participants who had ascites grade 2 ranged from 65.0% to 83.1% (Romanelli 2006; Caraceni 2018). Twenty trials reported the proportion of participants who had refractory or recurrent ascites: in 19 trials, all the participants had refractory or recurrent ascites (Ginès 1991; Strauss 1991; Bruno 1992; Ginès 1995; Lebrec 1996; Rossle 2000; Ginès 2002; Sanyal 2003; Salerno 2004; Licata 2009; Narahara 2011; Raza 2011; Bari 2012; Singh 2012a; Singh 2013; Hamdy 2014; Tuttolomondo 2016; Bureau 2017c; Rai 2017); in the remaining trial, the proportion of participants who had refractory or recurrent ascites was 85.0% (Acharya 1992). Forty‐one trials reported the proportion of participants who had alcohol‐related cirrhosis: in two trials, none of the participants had alcohol‐related cirrhosis (Chang 1997; Raza 2011); in four trials, all the participants had alcohol‐related cirrhosis (Gregory 1977; Stanley 1989b; Ljubici 1994; Schaub 1995); in the remaining 35 trials, the proportion of participants who had alcohol‐related cirrhosis ranged from 2.0% to 90.6% (Gines 1987; Salerno 1987; Chesta 1990; Ginès 1991; Strauss 1991; Acharya 1992; Bruno 1992; Hagege 1992; Sola 1994; Ginès 1995; Lebrec 1996; Fernandez‐Esparrach 1997; Mehta 1998; Gentilini 1999a; Rossle 2000; Ginès 2002; Moreau 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Singh 2006a; Singh 2006b; Lata 2007; Appenrodt 2008; Singh 2008; Licata 2009; Narahara 2011; Bari 2012; Singh 2012a; Singh 2013; Tuttolomondo 2016; Bureau 2017c; Rai 2017; Caraceni 2018; Sola 2018). Thirty‐three trials reported the proportion of participants who had viral‐related cirrhosis: in four trials, none of the participants had viral‐related cirrhosis (Gregory 1977; Stanley 1989b; Chesta 1990; Ljubici 1994); in one trial, all the participants had viral‐related cirrhosis (Chang 1997); in the remaining 28 trials, the proportion of participants who had viral‐related cirrhosis ranged from 5.6% to 95.0% (Gines 1987; Salerno 1987; Ginès 1991; Strauss 1991; Acharya 1992; Bruno 1992; Ginès 1995; Schaub 1995; Lebrec 1996; Gentilini 1999a; Moreau 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Singh 2006a; Singh 2006b; Appenrodt 2008; Singh 2008; Licata 2009; Narahara 2011; Raza 2011; Bari 2012; Singh 2012a; Singh 2013; Tuttolomondo 2016; Bureau 2017c; Rai 2017; Caraceni 2018; Sola 2018). Twenty‐two trials reported the proportion of participants who had autoimmune disease‐related cirrhosis: in 17 trials, none of the participants had autoimmune disease‐related cirrhosis (Gregory 1977; Salerno 1987; Ginès 1991; Ljubici 1994; Ginès 1995; Lebrec 1996; Chang 1997; Gentilini 1999a; Moreau 2002; Romanelli 2006; Singh 2006b; Appenrodt 2008; Licata 2009; Raza 2011; Singh 2013; Tuttolomondo 2016; Rai 2017); in the remaining five trials, the proportion of participants who had autoimmune disease‐related cirrhosis ranged from 2.5% to 12.0% (Chesta 1990; Singh 2006a; Singh 2008; Bari 2012; Singh 2012a). Only two trials reported whether the participants received antibiotic prophylaxis for spontaneous bacterial peritonitis (Ginès 2002; Caraceni 2018). In one trial, all participants received antibiotic prophylaxis (Ginès 2002); in the other trial, 19.3% of participants received antibiotic prophylaxis, but the reason for only a proportion of participants receiving antibiotic prophylaxis was not stated (Caraceni 2018). In 38 trials, patients with active other decompensation events such as active gastrointestinal bleeding, hepatorenal syndrome, or grade III or grade IV hepatic encephalopathy were excluded (Descos 1983; Gines 1987; Salerno 1987; Chesta 1990; Ginès 1991; Strauss 1991; Acharya 1992; Bruno 1992; Hagege 1992; Ljubici 1994; Sola 1994; Ginès 1995; Lebrec 1996; Chang 1997; Fernandez‐Esparrach 1997; Graziotto 1997; Mehta 1998; Gentilini 1999a; Ginès 2002; Moreau 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Singh 2006a; Singh 2006b; Singh 2008; Narahara 2011; Raza 2011; Al Sebaey 2012; Bari 2012; Singh 2012a; Singh 2013; Ali 2014; Hamdy 2014; Bureau 2017c; Rai 2017; Caraceni 2018; Sola 2018). In the remaining 11 trials, it was not clear whether patients with active other decompensation events were included (Gregory 1977; Fogel 1981; Mchutchison 1989; Stanley 1989b; Schaub 1995; Rossle 2000; Lata 2007; Appenrodt 2008; Licata 2009; Amin 2012; Tuttolomondo 2016). The interval between diagnosis and treatment was not reported in any of the trials.

A total of 21 interventions were compared in these trials. Forty‐two trials (2870 participants) reported one or more outcomes for this review (Gregory 1977; Fogel 1981; Descos 1983; Gines 1987; Salerno 1987; Chesta 1990; Ginès 1991; Strauss 1991; Acharya 1992; Hagege 1992; Ljubici 1994; Sola 1994; Ginès 1995; Schaub 1995; Lebrec 1996; Fernandez‐Esparrach 1997; Graziotto 1997; Mehta 1998; Gentilini 1999a; Rossle 2000; Ginès 2002; Moreau 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Singh 2006a; Singh 2006b; Lata 2007; Singh 2008; Licata 2009; Narahara 2011; Raza 2011; Bari 2012; Singh 2012a; Singh 2013; Ali 2014; Hamdy 2014; Tuttolomondo 2016; Bureau 2017c; Rai 2017; Caraceni 2018; Sola 2018). The important characteristics, potential effect modifiers, and follow‐up in each trial is reported in Table 2. Overall, there does not seem to be any systematic differences between the comparisons.

Open in table viewer
Table 2. Characteristics of included studies and potential effect modifiers

This table is too wide to be displayed in RevMan. This table can be found at: https://doi.org/10.5281/zenodo.3604600.

Funding: the source of funding for four trials was industries who would benefit from the results of the study (Stanley 1989b; Fernandez‐Esparrach 1997; Caraceni 2018; Sola 2018); 24 trials received no additional funding or were funded by neutral organisations with no vested interests in the results of the study (Descos 1983; Gines 1987; Ginès 1991; Sola 1994; Ginès 1995; Chang 1997; Gentilini 1999a; Ginès 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Singh 2006a; Singh 2006b; Appenrodt 2008; Singh 2008; Licata 2009; Bari 2012; Singh 2012a; Singh 2013; Ali 2014; Hamdy 2014; Tuttolomondo 2016; Bureau 2017c; Rai 2017); the source of funding for the remaining 21 trials was unclear (Gregory 1977; Fogel 1981; Salerno 1987; Mchutchison 1989; Chesta 1990; Strauss 1991; Acharya 1992; Bruno 1992; Hagege 1992; Ljubici 1994; Schaub 1995; Lebrec 1996; Graziotto 1997; Mehta 1998; Rossle 2000; Moreau 2002; Lata 2007; Narahara 2011; Raza 2011; Al Sebaey 2012; Amin 2012).

Excluded studies

The reasons for exclusion is provided in the Characteristics of excluded studies table.

Risk of bias in included studies

The risk of bias is summarised in Figure 3, Figure 4, and in Table 3. All the trials were at unclear or high risk of bias in at least one of the domains and were considered to be at high risk of bias overall.

Figure 3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 4
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Open in table viewer
Table 3. Risk of bias

Study name

Sequence generation

Allocation concealment

Blinding of patients and healthcare providers

Blinding of outcome assessors

Missing outcome bias

Selective outcome reporting

Overall risk of bias

Chang 1997

Low

Unclear

Unclear

Unclear

Unclear

Unclear

High

Chesta 1990

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Gines 1987

Low

Unclear

Unclear

Unclear

Unclear

Unclear

High

Hagege 1992

Low

Low

High

High

Unclear

Low

High

Salerno 1987

Unclear

Unclear

Unclear

Unclear

Low

Unclear

High

Schaub 1995

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Al Sebaey 2012

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Appenrodt 2008

Unclear

Unclear

Low

Low

Low

Unclear

High

Bari 2012

Low

Low

Low

Low

Unclear

Unclear

High

Hamdy 2014

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Lata 2007

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Moreau 2002

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Singh 2006a

Low

Low

High

High

Low

Low

High

Singh 2006b

Low

Low

High

High

Unclear

Low

High

Singh 2008

Low

Low

High

High

Low

Low

High

Ljubici 1994

Low

Unclear

Unclear

Unclear

Unclear

Unclear

High

Sola 1994

Low

Unclear

Unclear

Unclear

Unclear

Unclear

High

Strauss 1991

Low

Low

Unclear

Unclear

Unclear

Unclear

High

Bureau 2017c

Low

Unclear

Unclear

Unclear

Low

Unclear

High

Ginès 2002

Unclear

Low

Unclear

Unclear

Low

Unclear

High

Lebrec 1996

Unclear

Low

Unclear

Unclear

Unclear

Unclear

High

Narahara 2011

Low

Low

Unclear

Unclear

Low

Unclear

High

Rossle 2000

Unclear

Unclear

Unclear

Unclear

Low

Unclear

High

Salerno 2004

Unclear

Low

High

High

Low

Unclear

High

Sanyal 2003

Unclear

Low

Unclear

Unclear

Low

Unclear

High

Gregory 1977

Unclear

Unclear

Unclear

Unclear

Low

Unclear

High

Tuttolomondo 2016

Unclear

Unclear

Unclear

Unclear

Low

Unclear

High

Fogel 1981

Unclear

Unclear

High

High

Low

Unclear

High

Licata 2009

Low

Low

Unclear

Unclear

Low

Unclear

High

Bruno 1992

Low

Low

Unclear

Unclear

Low

Unclear

High

Graziotto 1997

Unclear

Low

Unclear

Unclear

Low

Unclear

High

Mehta 1998

Unclear

Unclear

High

High

Unclear

Unclear

High

Gentilini 1999a

Unclear

Unclear

Unclear

Unclear

Low

Unclear

High

Romanelli 2006

Low

Low

Unclear

Unclear

Low

Unclear

High

Caraceni 2018

Low

Low

High

High

Unclear

High

High

Ginès 1991

Low

Unclear

Unclear

Unclear

Unclear

Unclear

High

Ginès 1995

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Singh 2012a

Low

Low

Unclear

Unclear

Low

Low

High

Singh 2013

Low

Low

High

High

Low

Low

High

Fernandez‐Esparrach 1997

Unclear

Unclear

Unclear

Low

Low

Unclear

High

Acharya 1992

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Ali 2014

Low

Low

Low

Low

Unclear

Low

High

Amin 2012

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Descos 1983

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Rai 2017

Low

Low

High

High

Low

Unclear

High

Singh 2013

Low

Low

High

High

Low

Low

High

Singh 2013

Low

Low

High

High

Low

Low

High

Singh 2013

Low

Low

High

High

Low

Low

High

Singh 2013

Low

Low

High

High

Low

Low

High

Singh 2013

Low

Low

High

High

Low

Low

High

Raza 2011

Unclear

Unclear

Low

Low

Unclear

Unclear

High

Stanley 1989b

Unclear

Low

Unclear

Unclear

Low

Unclear

High

Sola 2018

Low

Low

Low

Low

High

Low

High

Mchutchison 1989

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Allocation

With regards to sequence generation, twenty‐two trials were at low risk of bias (Gines 1987; Ginès 1991; Strauss 1991; Bruno 1992; Hagege 1992; Ljubici 1994; Sola 1994; Chang 1997; Romanelli 2006; Singh 2006a; Singh 2006b; Singh 2008; Licata 2009; Narahara 2011; Bari 2012; Singh 2012a; Singh 2013; Ali 2014; Bureau 2017c; Rai 2017; Caraceni 2018; Sola 2018); the remaining 27 trials, which did not provide sufficient information, were at unclear risk of bias (Gregory 1977; Fogel 1981; Descos 1983; Salerno 1987; Mchutchison 1989; Stanley 1989b; Chesta 1990; Acharya 1992; Ginès 1995; Schaub 1995; Lebrec 1996; Fernandez‐Esparrach 1997; Graziotto 1997; Mehta 1998; Gentilini 1999a; Rossle 2000; Ginès 2002; Moreau 2002; Sanyal 2003; Salerno 2004; Lata 2007; Appenrodt 2008; Raza 2011; Al Sebaey 2012; Amin 2012; Hamdy 2014; Tuttolomondo 2016).

With regards to allocation concealment, twenty‐two trials were at low risk of bias (Stanley 1989b; Strauss 1991; Bruno 1992; Hagege 1992; Lebrec 1996; Graziotto 1997; Ginès 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Singh 2006a; Singh 2006b; Singh 2008; Licata 2009; Narahara 2011; Bari 2012; Singh 2012a; Singh 2013; Ali 2014; Rai 2017; Caraceni 2018; Sola 2018); the remaining 27 trials, which did not provide sufficient information, were at unclear risk of bias (Gregory 1977; Fogel 1981; Descos 1983; Gines 1987; Salerno 1987; Mchutchison 1989; Chesta 1990; Ginès 1991; Acharya 1992; Ljubici 1994; Sola 1994; Ginès 1995; Schaub 1995; Chang 1997; Fernandez‐Esparrach 1997; Mehta 1998; Gentilini 1999a; Rossle 2000; Moreau 2002; Lata 2007; Appenrodt 2008; Raza 2011; Al Sebaey 2012; Amin 2012; Hamdy 2014; Tuttolomondo 2016; Bureau 2017c).

Blinding

With regards to the blinding of patients and healthcare providers, five trials were at low risk of bias (Appenrodt 2008; Raza 2011; Bari 2012; Ali 2014; Sola 2018); 34 trials, which did not provide sufficient information, were at unclear risk of bias (Gregory 1977; Descos 1983; Gines 1987; Salerno 1987; Mchutchison 1989; Stanley 1989b; Chesta 1990; Ginès 1991; Strauss 1991; Acharya 1992; Bruno 1992; Ljubici 1994; Sola 1994; Ginès 1995; Schaub 1995; Lebrec 1996; Chang 1997; Fernandez‐Esparrach 1997; Graziotto 1997; Gentilini 1999a; Rossle 2000; Ginès 2002; Moreau 2002; Sanyal 2003; Romanelli 2006; Lata 2007; Licata 2009; Narahara 2011; Al Sebaey 2012; Amin 2012; Singh 2012a; Hamdy 2014; Tuttolomondo 2016; Bureau 2017c); the remaining 10 trials were at high risk of bias (Fogel 1981; Hagege 1992; Mehta 1998; Salerno 2004; Singh 2006a; Singh 2006b; Singh 2008; Singh 2013; Rai 2017; Caraceni 2018).

With regards to blinding of outcome assessors, six trials were at low risk of bias (Fernandez‐Esparrach 1997; Appenrodt 2008; Raza 2011; Bari 2012; Ali 2014; Sola 2018); 33 trials, which did not provide sufficient information, were at unclear risk of bias (Gregory 1977; Descos 1983; Gines 1987; Salerno 1987; Mchutchison 1989; Stanley 1989b; Chesta 1990; Ginès 1991; Strauss 1991; Acharya 1992; Bruno 1992; Ljubici 1994; Sola 1994; Ginès 1995; Schaub 1995; Lebrec 1996; Chang 1997; Graziotto 1997; Gentilini 1999a; Rossle 2000; Ginès 2002; Moreau 2002; Sanyal 2003; Romanelli 2006; Lata 2007; Licata 2009; Narahara 2011; Al Sebaey 2012; Amin 2012; Singh 2012a; Hamdy 2014; Tuttolomondo 2016; Bureau 2017c); the remaining 10 trials were at high risk of bias (Fogel 1981; Hagege 1992; Mehta 1998; Salerno 2004; Singh 2006a; Singh 2006b; Singh 2008; Singh 2013; Rai 2017; Caraceni 2018).

Incomplete outcome data

With regards to incomplete data, twenty‐three trials were at low risk of bias (Gregory 1977; Fogel 1981; Salerno 1987; Stanley 1989b; Bruno 1992; Fernandez‐Esparrach 1997; Graziotto 1997; Gentilini 1999a; Rossle 2000; Ginès 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Singh 2006a; Appenrodt 2008; Singh 2008; Licata 2009; Narahara 2011; Singh 2012a; Singh 2013; Tuttolomondo 2016; Bureau 2017c; Rai 2017); 25 trials were at unclear risk of bias (Descos 1983; Gines 1987; Mchutchison 1989; Chesta 1990; Ginès 1991; Strauss 1991; Acharya 1992; Hagege 1992; Ljubici 1994; Sola 1994; Ginès 1995; Schaub 1995; Lebrec 1996; Chang 1997; Mehta 1998; Moreau 2002; Singh 2006b; Lata 2007; Raza 2011; Al Sebaey 2012; Amin 2012; Bari 2012; Ali 2014; Hamdy 2014; Caraceni 2018), because it was not clear whether there were post‐randomisation dropouts or whether the post‐randomisation dropouts were related to the outcomes (if there were post‐randomisation dropouts); the remaining trial was at high risk of bias (Sola 2018), as the post‐randomisation dropouts were probably related to the intervention and the outcomes.

Selective reporting

Eight trials were at low risk of selective outcome reporting bias (Hagege 1992; Singh 2006a; Singh 2006b; Singh 2008; Singh 2012a; Singh 2013; Ali 2014; Sola 2018), as the important clinical outcomes expected to be reported in such trials were reported; 40 trials were at unclear risk of selective outcome reporting bias (Gregory 1977; Fogel 1981; Descos 1983; Gines 1987; Salerno 1987; Mchutchison 1989; Stanley 1989b; Chesta 1990; Ginès 1991; Strauss 1991; Acharya 1992; Bruno 1992; Ljubici 1994; Sola 1994; Ginès 1995; Schaub 1995; Lebrec 1996; Chang 1997; Fernandez‐Esparrach 1997; Graziotto 1997; Mehta 1998; Gentilini 1999a; Rossle 2000; Ginès 2002; Moreau 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Lata 2007; Appenrodt 2008; Licata 2009; Narahara 2011; Raza 2011; Al Sebaey 2012; Amin 2012; Bari 2012; Hamdy 2014; Tuttolomondo 2016; Bureau 2017c; Rai 2017), as a protocol published prior to recruitment was not available; the remaining trial was at high risk of selective outcome reporting bias (Caraceni 2018), as adverse events were clearly collected, but not reported adequately.

Other potential sources of bias

No other bias was noted in the trials.

Effects of interventions

See: Summary of findings for the main comparison ; Summary of findings 2

The network plots (where relevant) are available in Figure 1. The inconsistency factor plots (where relevant) are available in Figure 5. The differences in the fixed‐effect versus random‐effects model, where relevant, are available in Figure 6. The model fit is available in Table 4. The effect estimates are available in Table 5. A formal subgroup analysis was not possible for grade of ascites because the trials that provided this information included only grade 3 ascites or included a mixture of grade 2 and grade 3 ascites, i.e. there were no trials that included grade 2 ascites only. However, there was evidence of inconsistency in some outcomes when all studies were synthesised.

Figure 5
Inconsistency factor plots showing the inconsistency factors for the outcomes with direct and indirect evidence available for one or more comparisons. There was no evidence of inconsistency except for hospital stay. A higher resolution image of this picture is available at: http://doi.org/10.5281/zenodo.3531818.Abbreviations: Alb = Albumin
 AldoAnt = Aldosterone antagonists
 Fluid = Fluid replacement
 LoopD = Loop diuretics
 No active treatment = No active treatment
 OsmoD = Osmotic diuretics
 Paracen = Paracentesis
 PVShunt = Peritoneovenous shunt
 Reinf = Reinfusion
 Vasocons = Systemic vasoconstrictors
 Vasodil = Systemic vasodilator
 ThiazD = Thiazide diuretics
 TIPS = Transjugular intrahepatic portosystemic shunt

Inconsistency factor plots showing the inconsistency factors for the outcomes with direct and indirect evidence available for one or more comparisons. There was no evidence of inconsistency except for hospital stay. A higher resolution image of this picture is available at: http://doi.org/10.5281/zenodo.3531818.

Abbreviations:

Alb = Albumin
AldoAnt = Aldosterone antagonists
Fluid = Fluid replacement
LoopD = Loop diuretics
No active treatment = No active treatment
OsmoD = Osmotic diuretics
Paracen = Paracentesis
PVShunt = Peritoneovenous shunt
Reinf = Reinfusion
Vasocons = Systemic vasoconstrictors
Vasodil = Systemic vasodilator
ThiazD = Thiazide diuretics
TIPS = Transjugular intrahepatic portosystemic shunt

Figure 6
Forest plots showing the outcomes for which the random‐effects model were different from the fixed‐effect model. The more conservative random‐effects model was used. In this figure, mortality at maximal follow‐up, any adverse events (number of people), and resolution of ascites are shown. shows the remaining outcomes (other decompensation events and length of hospital stay), the other outcomes in which the fixed‐effect and random‐effects model were different. A higher resolution image of this picture is available at: http://doi.org/10.5281/zenodo.3531818.Abbreviations: Alb = Albumin
 AldoAnt = Aldosterone antagonists
 Fluid = Fluid replacement
 LoopD = Loop diuretics
 No active treatment = No active treatment
 OsmoD = Osmotic diuretics
 Paracen = Paracentesis
 PVShunt = Peritoneovenous shunt
 Reinf = Reinfusion
 Vasocons = Systemic vasoconstrictors
 Vasodil = Systemic vasodilator
 ThiazD = Thiazide diuretics
 TIPS = Transjugular intrahepatic portosystemic shunt

Forest plots showing the outcomes for which the random‐effects model were different from the fixed‐effect model. The more conservative random‐effects model was used. In this figure, mortality at maximal follow‐up, any adverse events (number of people), and resolution of ascites are shown. Figure 7 shows the remaining outcomes (other decompensation events and length of hospital stay), the other outcomes in which the fixed‐effect and random‐effects model were different. A higher resolution image of this picture is available at: http://doi.org/10.5281/zenodo.3531818.

Abbreviations:

Alb = Albumin
AldoAnt = Aldosterone antagonists
Fluid = Fluid replacement
LoopD = Loop diuretics
No active treatment = No active treatment
OsmoD = Osmotic diuretics
Paracen = Paracentesis
PVShunt = Peritoneovenous shunt
Reinf = Reinfusion
Vasocons = Systemic vasoconstrictors
Vasodil = Systemic vasodilator
ThiazD = Thiazide diuretics
TIPS = Transjugular intrahepatic portosystemic shunt

Figure 7
Forest plots showing the outcomes for which the random‐effects model were different from the fixed‐effect model. The more conservative random‐effects model was used. In this figure, other decompensation events and length of hospital stay are shown. shows the remaining outcomes (mortality at maximal follow‐up, any adverse events (number of people), and resolution of ascites), the other outcomes in which the fixed‐effect and random‐effects model were different. A higher resolution image of this picture is available at: http://doi.org/10.5281/zenodo.3531818.Abbreviations: Alb = Albumin
 AldoAnt = Aldosterone antagonists
 Fluid = Fluid replacement
 LoopD = Loop diuretics
 No active treatment = No active treatment
 OsmoD = Osmotic diuretics
 Paracen = Paracentesis
 PVShunt = Peritoneovenous shunt
 Reinf = Reinfusion
 Vasocons = Systemic vasoconstrictors
 Vasodil = Systemic vasodilator
 ThiazD = Thiazide diuretics
 TIPS = Transjugular intrahepatic portosystemic shunt

Forest plots showing the outcomes for which the random‐effects model were different from the fixed‐effect model. The more conservative random‐effects model was used. In this figure, other decompensation events and length of hospital stay are shown. Figure 6 shows the remaining outcomes (mortality at maximal follow‐up, any adverse events (number of people), and resolution of ascites), the other outcomes in which the fixed‐effect and random‐effects model were different. A higher resolution image of this picture is available at: http://doi.org/10.5281/zenodo.3531818.

Abbreviations:

Alb = Albumin
AldoAnt = Aldosterone antagonists
Fluid = Fluid replacement
LoopD = Loop diuretics
No active treatment = No active treatment
OsmoD = Osmotic diuretics
Paracen = Paracentesis
PVShunt = Peritoneovenous shunt
Reinf = Reinfusion
Vasocons = Systemic vasoconstrictors
Vasodil = Systemic vasodilator
ThiazD = Thiazide diuretics
TIPS = Transjugular intrahepatic portosystemic shunt

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Table 4. Model fit

Mortality at maximal follow‐up

Fixed‐effect model

Random‐effects model

Inconsistency model

Dbar

255.1

253.7

255.3

DIC

297.9

299.2

303.1

pD

42.8

45.5

47.75

Any adverse events (number of people)

Fixed‐effect model

Random‐effects model

Inconsistency model

Dbar

38.89

39.75

‐

DIC

46.75

48.72

‐

pD

7.862

8.96

‐

Liver transplantation at maximal follow‐up

Fixed‐effect model

Random‐effects model

Inconsistency model

Dbar

54.83

54.1

‐

DIC

64.51

65.98

‐

pD

9.684

11.88

‐

Resolution of ascites at maximal follow‐up (by ultrasound)

Fixed‐effect model

Random‐effects model

Inconsistency model

Dbar

182.7

135

‐

DIC

206.4

165.3

‐

pD

23.73

30.24

‐

Other features of decompensation at maximal follow‐up

Fixed‐effect model

Random‐effects model

Inconsistency model

Dbar

258

258.1

253

DIC

293.9

294

294.7

pD

35.89

35.92

41.71

Length of hospital stay (days) (all admissions until maximal follow‐up)

Fixed‐effect model

Random‐effects model

Inconsistency model

Dbar

152.7

122.8

122.7

DIC

173.7

147.2

147.3

pD

20.95

24.39

24.56

Treatment costs

Fixed‐effect model

Random‐effects model

Inconsistency model

Dbar

4961

34.09

‐

DIC

4963

38.08

‐

pD

2.023

3.998

‐

Dbar = posterior mean of deviance

DIC = deviance information criteria

pD = effective number of parameters or leverage

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Table 5. Effect estimates (network meta‐analysis)

This table is too wide to be displayed in RevMan. This table can be found at: https://doi.org/10.5281/zenodo.3604602

The table provides the effect estimates of each pairwise comparison for the different outcomes. The top half of the table indicates the effect estimates from the direct comparisons. The bottom half of the table indicates the effect estimates from the network meta‐analysis. For network meta‐analysis, to identify the effect estimate of a comparison, say A versus B, look at the cell that occupies the row corresponding to intervention A and the column corresponding to intervention B for the direct effect estimate. If that cell is empty (indicated by a '‐'), look at the row corresponding to intervention B and the column corresponding to intervention A. Take the inverse of this number (i.e. 1/number) to arrive at the treatment effect of A versus B. For direct comparisons, this is exactly the opposite; look at the cell that occupies the column corresponding to intervention A and the row corresponding to intervention B for the direct effect estimate. If that cell is empty, look at the column corresponding to intervention B and the row corresponding to intervention A. Take the inverse of this number to arrive at the treatment effect of A versus B. If the cell corresponding to B versus A is also missing in direct comparisons, this means that there was no direct comparison.

Statistically significant results are shown in italics.

The 95% credible intervals of the probability ranks were wide and included 0 and 1 in most comparisons for all the primary and secondary outcomes. This was probably because of the sparse data from small trials. Therefore, we did not present the ranking probabilities (in a table), rankograms, and SUCRA plots as we considered that presenting this information would be unhelpful and potentially misleading and would ignore the differences in systematic errors in the trials.

The certainty of evidence was low or very low for all the comparisons. This was because most of the trials included in the comparison were at unclear or high risk of bias for at least one risk of bias domain at the outcome level (downgraded one level) and the sample size was small (downgraded one level). This resulted in low‐certainty evidence. In comparisons where the wide credible intervals overlapped significant clinical effect and no effect, we downgraded one more level for imprecision (downgraded one level). There was also evidence of heterogeneity (called inconsistency in the GRADE system; not to be confused with inconsistency in direct and indirect estimates in the context of network meta‐analysis) for resolution of ascites and other decompensation events (downgraded one level)

Mortality at maximal follow‐up

Thirty‐four trials (2548 participants) reported mortality at maximal follow‐up (Gregory 1977; Fogel 1981; Descos 1983; Gines 1987; Salerno 1987; Chesta 1990; Ginès 1991; Acharya 1992; Hagege 1992; Ljubici 1994; Sola 1994; Ginès 1995; Lebrec 1996; Graziotto 1997; Gentilini 1999a; Rossle 2000; Ginès 2002; Moreau 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Singh 2006a; Singh 2006b; Singh 2008; Licata 2009; Narahara 2011; Bari 2012; Singh 2012a; Singh 2013; Ali 2014; Bureau 2017c; Rai 2017; Caraceni 2018; Sola 2018). A total of 18 treatments were compared in these trials. Two trials were not connected to the network because they were the only trials for the comparisons and had zero events in one of the intervention groups (Acharya 1992; Ali 2014), and thus were excluded from the analysis. The network had 16 connected treatments (32 trials; 2448 participants). There was no evidence of inconsistency according to model fit, inconsistency factor, and the 'between‐design' variance 0.16 (95% CrI 0.00 to 10.02). The random‐effects model was used because it was more conservative, even though the model fit was similar to the fixed‐effect model. The 'between‐study variance' was 0.02 (95% CrI 0.00 to 0.27).

There was no evidence of differences between interventions in any of the direct comparisons or in the comparisons included in the network meta‐analysis (i.e. there was no statistically significant difference in any of the comparisons) (Table 5) (very low‐certainty evidence; summary of findings Table 2). The sensitivity analysis indicated that the different scenarios (best‐best and worst‐worst scenarios) for imputing missing data showed different interpretation of results; therefore, the results have to be interpreted with caution.

There was also no evidence of differences between the comparisons not included in the network meta‐analysis.

  • Aldosterone antagonists plus paracentesis plus fluid replacement (0/20; 0%) versus aldosterone antagonists plus loop diuretics (1/20; 5%) (1 trial; 40 participants; very low‐certainty evidence);

  • Systemic vasoconstrictors (1/30; 3.3%) versus no active intervention (0/30; 0%) (1 trial; 60 participants; very low‐certainty evidence).

Serious adverse events

Fourteen trials (761 participants) reported serious adverse events (with respect to number of people) (Acharya 1992; Hagege 1992; Ljubici 1994; Singh 2006a; Singh 2006b; Lata 2007; Singh 2008; Narahara 2011; Raza 2011; Singh 2012a; Singh 2013; Ali 2014; Rai 2017; Sola 2018). A total of 14 treatments were compared in these trials. Ten trials were not connected to the network because they had zero events in both intervention groups (Hagege 1992; Singh 2006a; Singh 2006b; Singh 2008; Narahara 2011; Raza 2011; Singh 2012a; Singh 2013; Ali 2014; Rai 2017); two trials were not connected to the network because they were the only trials for the comparison and had zero events in one of the intervention groups (Ljubici 1994; Lata 2007); the remaining trials had no common treatments, and therefore were not connected (Acharya 1992; Sola 2018). Only two treatments were compared in each of the remaining trials (Acharya 1992; Sola 2018). Therefore, random‐effects, network meta‐analysis, checking for inconsistency, or subgroup analyses were not applicable.

There was no evidence of differences in any of the direct comparisons for which it was possible to calculate the effect estimates (i.e. there was no statistically significant difference in any of the comparisons).

  • Aldosterone antagonists plus paracentesis plus fluid replacement versus aldosterone antagonists plus loop diuretics: OR 0.68 (95% CrI 0.11 to 3.83; 1 trial; 40 participants; very low‐certainty evidence);

  • Aldosterone antagonists plus loop diuretics plus systemic vasodilator versus aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus systemic vasodilator: OR 0.84 (95% CrI 0.46 to 1.55; 1 trial; 173 participants; very low‐certainty evidence);

  • Aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement (0/10; 0%) versus aldosterone antagonists plus loop diuretics (1/11; 9.1%) (1 trial; 21 participants; very low‐certainty evidence);

  • Paracentesis plus systemic vasoconstrictors (0/84; 0%) versus paracentesis plus fluid replacement (1/85; 1.2%) (4 trials; 169 participants; very low‐certainty evidence).

There was no change in the results by using the best‐worst and worst‐best scenarios for imputing missing data.

Two trials (111 participants) reported serious adverse events (with respect to number of events) (Salerno 1987; Ginès 2002). A total of three treatments were compared in these trials. One trial was not connected to the network because it was the only trial for the comparison and had zero events in one of the intervention groups (Ginès 2002). Only two treatments were compared in the remaining trial (Salerno 1987; 41 participants). Therefore, random‐effects, network meta‐analysis, checking for inconsistency, or subgroup analyses were not applicable.

There was no evidence of differences in the only direct comparison for which it was possible to calculate the effect estimates (i.e. there was no statistically significant difference): aldosterone antagonists plus loop diuretics versus paracentesis plus fluid replacement: rate ratio: 1.30 (95% CrI 0.27 to 7.16; 1 trial; 41 participants; very low‐certainty evidence; summary of findings Table 2). In the remaining comparison, transjugular intrahepatic portosystemic shunt versus paracentesis plus fluid replacement, there were 10 serious advents in 35 participants receiving transjugular intrahepatic portosystemic shunt (28.6 serious adverse events per 100 participants) compared to no serious adverse events in 35 participants receiving paracentesis plus fluid replacement (1 trial; 70 participants; very low‐certainty evidence).

Health‐related quality of life

One trial (431 participants) reported health‐related quality of life (EQ‐5D) (Caraceni 2018). For EQ‐5D, a higher score indicates better health‐related quality of life. A total of two treatments were compared in this trial. Since only one trial reported the outcome, random‐effects, network meta‐analysis, checking for inconsistency, or subgroup analyses were not applicable. Aldosterone antagonists plus loop diuretics plus albumin had better health‐related quality of life than aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement: MD 0.06 (95% CrI 0.03 to 0.09; 1 trial; 431 participants; low‐certainty evidence). The standard deviation was reported in the trial: therefore, sensitivity analysis of excluding trials in which standard deviations were imputed was not applicable.

Any adverse events

Eight trials (462 participants) reported any adverse events (with respect to number of people) (Chesta 1990; Hagege 1992; Singh 2006a; Singh 2006b; Singh 2008; Narahara 2011; Bari 2012; Sola 2018). A total of six treatments were compared in these trials. Two trials were not connected to the network because they were the only trials for the comparisons and had zero events in one of the intervention groups (Narahara 2011) or had unconnected treatments (Sola 2018). The network had three connected treatments (6 trials; 229 participants). There were no triangular or quadrangular loops; therefore, inconsistency was not checked. The random‐effects model was used because it was more conservative, even though the model fit was similar to the fixed‐effect model. The 'between‐study variance' was 0.37 (95% CrI 0.00 to 10.82).

There was no evidence of differences in any of the direct comparisons or network meta‐analysis (i.e. there was no statistically significant difference in any of the comparisons included in the network meta‐analysis) (Table 5) (very low‐certainty evidence; summary of findings Table 2). There was no change in the results by using the best‐best and worst‐worst scenarios for imputing missing data.

The results of the remaining two comparisons which could not be included in the network meta‐analysis are as follows.

  • 10 participants among 30 participants (10/30; 33.3%) receiving transjugular intrahepatic portosystemic shunt compared to no participant of 30 participants (0/30; 05) receiving paracentesis plus fluid replacement developed 'any adverse events' (1 trial; 60 participants; very low‐certainty evidence).

  • There was no evidence of differences between systemic vasoconstrictors plus albumin versus no active intervention OR 0.45 (95% CrI 0.05 to 2.61; 1 trial; 173 participants; very low‐certainty evidence).

Five trials (314 participants) reported any adverse events (number of events) (Chesta 1990; Bari 2012; Singh 2013; Rai 2017; Sola 2018). A total of 10 treatments were compared in these trials. Two trials were not connected to the network because of unconnected treatments (Rai 2017;Sola 2018). The network had six connected treatments (3 trials; 116 participants). There was no evidence of inconsistency according to model fit and the 'between‐design' variance 0.17 (95% CrI 0.00 to 3.49). The inconsistency factor plot could not be obtained since there was only one trial for the closed loops and heterogeneity could not be calculated. The fixed‐effect model was used because there was only one trial for each of the comparisons.

The following direct comparisons were statistically significant (both comparisons not included in the network meta‐analysis because of unconnected treatments):

  • Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus paracentesis plus fluid replacement versus aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement: rate ratio 0.07 (95% CrI 0.00 to 0.47; 1 trial; 25 participants; low‐certainty evidence);

  • Systemic vasoconstrictors plus albumin versus no active treatment: rate ratio 1.17 (95% CrI 1.03 to 1.33; 1 trial; 173 participants; low‐certainty evidence).

There was no evidence of differences between the treatments in the remaining direct comparisons (i.e. the remaining direct comparisons were not statistically significant) or in the network meta‐analysis (Table 5) (very low‐certainty evidence; summary of findings Table 2). The sensitivity analysis indicated that the different scenarios (best‐worst and worst‐best scenarios) for imputing missing data showed different interpretation of results; therefore, the results have to be interpreted with caution.

Liver transplantation at maximal follow‐up

Nineteen trials (1568 participants) reported liver transplantation at maximal follow‐up (Fogel 1981; Hagege 1992; Graziotto 1997; Rossle 2000; Ginès 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Singh 2006a; Singh 2006b; Singh 2008; Narahara 2011; Bari 2012; Singh 2012a; Singh 2013; Bureau 2017c; Rai 2017; Caraceni 2018; Sola 2018). A total of 14 treatments were compared in these trials. Five trials were not connected to the network because they had zero events in both intervention groups (Fogel 1981; Hagege 1992; Singh 2012a; Singh 2013; Rai 2017); three trials were not connected to the network because of unconnected treatments (Romanelli 2006; Caraceni 2018; Sola 2018). The network had four connected treatments (11 trials; 596 participants). There were no triangular or quadrangular loops; therefore, inconsistency was not checked. The fixed‐effect model was used because it had equivalent results and model fit to the random‐effects model.

There was no evidence of differences in any of the direct comparisons or network meta‐analysis (i.e. there was no statistically significant difference in any of the comparisons) (Table 5) (very low‐certainty evidence; summary of findings Table 2). There was no change in the results by using the best‐worst and worst‐best scenarios for imputing missing data.

The effect estimates in the comparisons with unconnected treatments were as follows.

  • Aldosterone antagonists plus loop diuretics plus albumin versus aldosterone antagonists plus loop diuretics: HR 0.22 (95% CrI 0.01 to 1.99; 1 trial; 100 participants; very low‐certainty evidence);

  • Aldosterone antagonists plus loop diuretics plus albumin versus aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement: HR 1.03 (95% CrI 0.54 to 2.00; 1 trial; 431 participants; very low‐certainty evidence);

  • Systemic vasoconstrictors plus albumin versus no active intervention: HR 1.44 (95% CrI 0.96 to 2.15; 1 trial; 173 participants; very low‐certainty evidence).

The number of people who underwent liver transplantation in the trials with zero events are as follows.

  • Aldosterone antagonists plus loop diuretics (0/27; 0%) versus paracentesis plus fluid replacement (0/26; 0%) (1 trial; 53 participants; very low‐certainty evidence);

  • Aldosterone antagonists plus loop diuretics (0/61; 0%) versus loop diuretics (0/29; 0%) (1 trial; 90 participants; very low‐certainty evidence);

  • Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors (0/35; 0%) versus aldosterone antagonists plus loop diuretics (0/35; 0%) (2 trials; 70 participants; very low‐certainty evidence);

  • Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus systemic vasodilator (0/15; 0%) versus aldosterone antagonists plus loop diuretics (0/15; 0%) (1 trial; 30 participants; very low‐certainty evidence);

  • Aldosterone antagonists plus loop diuretics plus systemic vasodilator (0/15; 0%) versus aldosterone antagonists plus loop diuretics (0/15; 0%) (1 trial; 30 participants; very low‐certainty evidence);

  • Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus paracentesis plus fluid replacement (0/13; 0%) versus aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement (0/12; 0%) (1 trial; 25 participants; very low‐certainty evidence);

  • Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus systemic vasodilator (0/15; 0%) versus aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors (0/15; 0%) (1 trial; 30 participants; very low‐certainty evidence);

  • Aldosterone antagonists plus loop diuretics plus systemic vasodilator (0/15; 0%) versus aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors (0/15; 0%) (1 trial; 30 participants; very low‐certainty evidence);

  • Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus systemic vasodilator (0/15; 0%) versus aldosterone antagonists plus loop diuretics plus systemic vasodilator (0/15; 0%) (1 trial; 30 participants; very low‐certainty evidence).

Resolution of ascites at maximal follow‐up

None of the trials reported symptomatic resolution of ascites (for example, resolution of shortness of breath) at maximal follow‐up. Twenty trials (1217 participants) reported resolution of ascites (by ultrasound) at maximal follow‐up (Gregory 1977; Descos 1983; Salerno 1987; Chesta 1990; Strauss 1991; Hagege 1992; Lebrec 1996; Fernandez‐Esparrach 1997; Graziotto 1997; Gentilini 1999a; Ginès 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Licata 2009; Narahara 2011; Singh 2012a; Singh 2013; Bureau 2017c; Rai 2017). A total of 14 treatments were compared in these trials. Two trials were not connected to the network because they were the only trials for the comparison and had zero events in one of the intervention groups (Graziotto 1997; Rai 2017) and another trial was not connected because of unconnected treatments. One more trial had four arms with zero events in all four arms (Singh 2013). One comparison could be included in the network meta‐analysis as there were some events in the remaining trials of the same comparison, but the other comparisons could not be included (Singh 2013). The network had nine connected treatments (17 trials; 1007 participants). There were no triangular or quadrangular loops; therefore, inconsistency was not checked. The random‐effects model was used because it was more conservative and had better model fit. The 'between‐study variance' was 2.60 (95% CrI 0.68 to 12.29).

The following direct comparisons which could be estimated were in favour of:

  • Transjugular intrahepatic portosystemic shunt versus paracentesis plus fluid replacement: HR 8.37 (95% CrI 1.97 to 62.68; 6 trials; 392 participants; very low‐certainty evidence);

  • Aldosterone antagonists plus paracentesis plus fluid replacement versus paracentesis plus fluid replacement alone: HR 30.63 (95% CrI 5.06 to 692.98; 1 trial; 36 participants; low‐certainty evidence);

  • No active treatment versus aldosterone antagonists plus loop diuretics: HR 0.15 (95% CrI 0.04 to 0.43 ; 1 trial; 43 participants; low‐certainty evidence) (i.e. aldosterone antagonists plus loop diuretics versus no active treatment: HR 6.67 (95% CrI 2.33 to 25));

  • Loop diuretics versus aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement: HR 1.90 (95% CrI 1.03 to 3.76 ; 1 trial; 84 participants; low‐certainty evidence).

There was no evidence of differences between the treatments in the remaining direct comparisons (i.e. the remaining direct comparisons were not statistically significant) (Table 5) (very low‐certainty evidence). In the network meta‐analysis, the following comparisons were statistically significant:

  • Transjugular intrahepatic portosystemic shunt versus paracentesis plus fluid replacement: HR 9.44 (95% CrI 1.93 to 62.68) (similar effect as in direct comparison; very low‐certainty evidence)

There was no evidence of differences between the treatments in the remaining comparisons in the network meta‐analysis (Table 5) (very low‐certainty evidence; summary of findings Table 2). There was no change in the results by using the best‐worst and worst‐best scenarios for imputing missing data.

The effect estimates in the comparisons with unconnected treatments were as follows.

  • Aldosterone antagonists versus paracentesis plus reinfusion: HR 1.11 (95% CrI 0.69 to 1.79; 1 trial; 131 participants; very low‐certainty evidence)

The number of people who had resolution of ascites in the trials with zero events are as follows.

  • Paracentesis plus reinfusion (2/12; 16.7%) versus paracentesis plus fluid replacement (0/12; 0%) (1 trial; 24 participants; very low‐certainty evidence)

  • Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus systemic vasodilator (0/15; 0%) versus aldosterone antagonists plus loop diuretics (0/15; 0%) (1 trial; 30 participants; very low‐certainty evidence)

  • Aldosterone antagonists plus loop diuretics plus systemic vasodilator (0/15; 0%) versus aldosterone antagonists plus loop diuretics (0/15; 0%) (1 trial; 30 participants; very low‐certainty evidence)

  • Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus paracentesis plus fluid replacement (5/13; 38.5%) versus aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement (0/12; 0%) (1 trial; 25 participants; very low‐certainty evidence)

  • Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus systemic vasodilator (0/15; 0%) versus aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors (0/15; 0%) (1 trial; 30 participants; very low‐certainty evidence)

  • Aldosterone antagonists plus loop diuretics plus systemic vasodilator (0/15; 0%) versus aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors (0/15; 0%) (1 trial; 30 participants; very low‐certainty evidence)

  • Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus systemic vasodilator (0/15; 0%) versus aldosterone antagonists plus loop diuretics plus systemic vasodilator (0/15; 0%) (1 trial; 30 participants; very low‐certainty evidence)

Other features of decompensation at maximal follow‐up

Twenty‐seven trials (1821 participants) reported other features of decompensation at maximal follow‐up (Gregory 1977; Fogel 1981; Gines 1987; Salerno 1987; Chesta 1990; Ginès 1991; Strauss 1991; Acharya 1992; Hagege 1992; Sola 1994; Ginès 1995; Lebrec 1996; Gentilini 1999a; Rossle 2000; Ginès 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Lata 2007; Singh 2008; Licata 2009; Narahara 2011; Bari 2012; Singh 2013; Bureau 2017c; Rai 2017; Sola 2018). A total of 15 treatments were compared in these trials. Two trials were not connected to the network because they were the only trials for the comparisons and had zero events in one of the intervention groups (Acharya 1992; Rai 2017). The network had 13 connected treatments (25 trials; 1756 participants). There was no evidence of inconsistency according to the inconsistency factor plot or model fit. We could not obtain convergence for the design‐by‐treatment analysis. The random‐effects model was used because it was more conservative and had a large between‐study variance of 6.25 (95% CrI 0.02 to 23.78), even though the model fit was similar to the fixed‐effect model.

The following direct comparisons were in favour of:

  • Aldosterone antagonists plus loop diuretics versus paracentesis plus fluid replacement: rate ratio 2.04 (95% CrI 1.39 to 3.08; 4 trials; 242 participants; very low‐certainty evidence) (i.e. paracentesis plus fluid replacement versus aldosterone antagonists plus loop diuretics: rate ratio 0.49 (95% CrI 0.72 to 0.32))

  • Aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement versus aldosterone antagonists plus loop diuretics: rate ratio 0.48 (95% CrI 0.29 to 0.77 ; 2 trials; 102 participants; low‐certainty evidence)

  • Aldosterone antagonists plus paracentesis plus fluid replacement versus aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors: 7/12 (0.6 other decompensation events per participant) versus 0/13 (no decompensation events per participant) (1 trial; 15 participants).

There was no evidence of differences between the treatments in the remaining direct comparisons (i.e. the remaining direct comparisons were not statistically significant) (Table 5) (very low‐certainty). In the network meta‐analysis, the following comparisons were in favour of:

  • Aldosterone antagonists plus loop diuretics versus paracentesis plus fluid replacement: rate ratio 2.04 (95% CrI 1.37 to 3.10) (i.e. paracentesis plus fluid replacement versus aldosterone antagonists plus loop diuretics: rate ratio 0.49 (95% CrI 0.73 to 0.32))

  • Aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement versus aldosterone antagonists plus loop diuretics: rate ratio 0.51 (95% CrI 0.32 to 0.80)

  • Transjugular intrahepatic portosystemic shunt versus aldosterone antagonists plus loop diuretics: rate ratio 0.57 (95% CrI 0.35 to 0.92)

  • Loop diuretics versus aldosterone antagonists plus loop diuretics: rate ratio 0.47 (95% CrI 0.22 to 0.96)

  • Aldosterone antagonists plus loop diuretics plus peritoneovenous shunt versus aldosterone antagonists plus loop diuretics: rate ratio 0.41 (95% CrI 0.23 to 0.73)

  • Systemic vasoconstrictors plus albumin versus aldosterone antagonists plus loop diuretics plus peritoneovenous shunt: rate ratio 4.65 (95% CrI 1.06 to 20.84) i..e. aldosterone antagonists plus loop diuretics plus peritoneovenous shunt versus systemic vasoconstrictors plus albumin: rate ratio: 0.22 (95% CrI 0.05 to 0.94).

There was no evidence of differences between the treatments in the remaining comparisons in the network meta‐analysis (Table 5) (very low‐certainty evidence; summary of findings Table 2).

The number of decompensation events in the trials with zero events are as follows.

  • Aldosterone antagonists plus paracentesis plus fluid replacement (0/20; 0 events) versus aldosterone antagonists plus loop diuretics (3/20; 15 events per 100 participants) (1 trial; 40 participants; very low‐certainty evidence)

  • Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus paracentesis plus fluid replacement (0/13; 0 events) versus aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement (7/12; 58.3 events per 100 participants) (1 trial; 25 participants; very low‐certainty evidence).

Length of hospital stay (days)

Fifteen trials (1086 participants) reported length of hospital stay (days) (all admissions until maximal follow‐up) (Fogel 1981; Descos 1983; Gines 1987; Chesta 1990; Ginès 1991; Hagege 1992; Ginès 1995; Schaub 1995; Gentilini 1999a; Rossle 2000; Moreau 2002; Salerno 2004; Licata 2009; Tuttolomondo 2016; Bureau 2017c). A total of 10 treatments were compared in these trials. One trial was not connected to the network because it had treatments unconnected to network (Descos 1983). The network had eight connected treatments. There was evidence of inconsistency according to the 'between‐design' variance 11.04 (95% CrI 0.05 to 24.30) and inconsistency factor, but not by model fit; therefore, there is uncertainty in the validity of NMA results: direct comparisons are more reliable. The random‐effects model was used because it had better model fit. The 'between‐study variance' was 20.10 (95% CrI 8.86 to 24.79).

The following direct comparisons were in favour of:

  • Aldosterone antagonists plus loop diuretics versus paracentesis plus fluid replacement: MD 14.00 days (95% CrI 9.19 to 18.52; 4 trials; 218 participants; low‐certainty evidence), i.e. paracentesis plus fluid replacement versus aldosterone antagonists plus loop diuretics versus paracentesis (MD ‐14.00 days (95% CrI ‐18.52 to ‐9.19)

  • Aldosterone antagonists plus loop diuretics plus albumin versus aldosterone antagonists plus loop diuretics: MD ‐9.28 days (95% CrI ‐14.11 to ‐4.40; 1 trial; 126 participants; low‐certainty evidence).

There was no evidence of differences between the treatments in the remaining direct comparisons (i.e. the remaining direct comparisons were not statistically significant) (Table 5). In the network meta‐analysis, the following comparisons were in favour of:

  • Aldosterone antagonists plus loop diuretics versus paracentesis plus fluid replacement: MD 11.81 days (95% CrI 6.92 to 16.67; low‐certainty evidence), i.e. paracentesis plus fluid replacement versus aldosterone antagonists plus loop diuretics versus paracentesis (MD ‐11.81 days (95% CrI ‐16.67 to ‐6.92)

  • Paracentesis plus systemic vasoconstrictors versus aldosterone antagonists plus loop diuretics: MD ‐11.60 days (95% CrI ‐21.67 to ‐1.68; low‐certainty evidence)

  • Transjugular intrahepatic portosystemic shunt versus aldosterone antagonists plus loop diuretics: MD ‐17.25 days (95% CrI ‐28.47 to ‐6.17; low‐certainty evidence).

There was no evidence of differences between the treatments in the remaining comparisons in the network meta‐analysis (Table 5). There was no imputation of mean or standard deviation in the trials. Therefore, sensitivity analysis excluding trials in which mean or standard deviation were to be imputed was not applicable.

Work days lost

None of the trials reported work days lost.

Treatment costs

Four trials (150 participants) reported treatment costs (Mehta 1998; Singh 2006a; Singh 2008; Hamdy 2014). We used an international exchange rate based on purchasing power parities (PPP) to convert cost estimates to USA dollars (USD), and we used the gross domestic product (GDP) deflators (or implicit price deflators for GDP) to convert cost estimates to 2018 USD using PPP conversion rates and GDP deflator values available from the International Monetary Fund in the World Economic Outlook Database (www.imf.org/external/data.htm (accessed in July 2019)).

A total of three treatments were compared in the four trials. All the trials were connected to the network (after imputation of standard deviation for one trial). There were no triangular or quadrangular loops; therefore, inconsistency was not checked. The random‐effects model was used because of the model fit and because the random‐effects model was the more conservative model. The 'between‐study variance' was 2,458,624 (95% CrI 265,431 to 64,689,849). Given the extremely high between‐study variance, we have presented the results in a table, without meta‐analysing the results.

Treatment costs for paracentesis plus systemic vasoconstrictors was lower than that for paracentesis plus fluid replacement in all the three trials that reported this information (Table 6). For the other comparison, paracentesis plus reinfusion versus paracentesis plus fluid replacement, the standard deviation was not reported; therefore, it was not clear whether there were differences in treatment costs between the two interventions.

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Table 6. Treatment costs (tabular results without meta‐analysis)

Study name

Comparison

Mean in intervention group

Standard deviation in intervention group

Number of participants in intervention group

Mean in control group

Standard deviation in control group

Number of participants in control group

Mean difference and 95% confidence intervals (according to Review Manager formula)

Hamdy 2014

Paracentesis plus systemic vasoconstrictors versus paracentesis plus fluid replacement

10.5 USD

0.1 USD

25

856.1 USD

119.6 USD

25

‐845.60 (95% CI ‐892.48 to ‐798.72)

Singh 2006a

Paracentesis plus systemic vasoconstrictors versus paracentesis plus fluid replacement

1629.0 USD

76.7 USD

20

3368.0 USD

82.5 USD

20

‐1739.00 (95% CI ‐1788.37 to ‐1689.63)

Singh 2008

Paracentesis plus systemic vasoconstrictors versus paracentesis plus fluid replacement

29.4 USD

2.7 USD

20

105.7 USD

25.4 USD

20

‐76.30 (95% CI ‐87.49 to ‐65.11)

Mehta 1998

Paracentesis plus reinfusion versus paracentesis plus fluid replacement

295 USD

not reported

10

440 USD

Not reported

10

‐ 105; no information to calculate the 95% confidence intervals

Abbreviations:

USD = United States Dollar
CI = confidence intervals

Subgroup analysis

Data were sufficient to perform only the following subgroup analysis: duration of follow‐up (short‐term, medium‐term, and long‐term). There were no subgroup differences for any of the outcomes where there were at least two different subgroups represented in the analyses.

There were insufficient data for the remaining subgroup analyses or only one subgroup was represented in the analyses. Although a formal test for subgroup differences was not relevant for grade of ascites, as the trials included either only ascites 3 or a mixture of ascites 2 and ascites 3 (or did not provide information on the grade of ascites), we have presented the subgroup estimates of grade 3 ascites only in Table 7, when possible. Similarly, we have presented the results for recurrent and refractory ascites only in Table 8, when possible. Some comparisons became statistically nonsignificant, as could be expected when fewer than 50% trials were included for the analysis, but there were no major differences that would have resulted in alterations in the overall interpretation of the results.

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Table 7. Effect estimates (Subgroup: grade 3 ascites only)

This table is too wide to be displayed in RevMan. This table can be found at: https://doi.org/10.5281/zenodo.3604780.

The table provides the network meta‐analysis effect estimates for the subgroup of grade 3 ascites only of each pairwise comparison for the different outcomes. To identify the effect estimate of a comparison, say A versus B, look at the cell that occupies the row corresponding to intervention A and the column corresponding to intervention B for the direct effect estimate. If that cell is empty (indicated by a '‐'), look at the row corresponding to intervention B and the column corresponding to intervention A. Take the inverse of this number (i.e. 1/number) to arrive at the treatment effect of A versus B.

Statistically significant results are shown in italics.

Abbreviations:

HR = hazard ratio; OR = odds ratio

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Table 8. Effect estimates (Subgroup: refractory or recurrent ascites only)

This table is too wide to be displayed in RevMan. This table can be found at: https://doi.org/10.5281/zenodo.3604784.

The table provides the network meta‐analysis effect estimates for the subgroup of refractory or recurrent ascites only of each pairwise comparison for the different outcomes. To identify the effect estimate of a comparison, say A versus B, look at the cell that occupies the row corresponding to intervention A and the column corresponding to intervention B for the direct effect estimate. If that cell is empty (indicated by a '‐'), look at the row corresponding to intervention B and the column corresponding to intervention A. Take the inverse of this number (i.e. 1/number) to arrive at the treatment effect of A versus B.

Statistically significant results are shown in italics.

Abbreviations:

HR = hazard ratio
OR = odds ratio

Sensitivity analysis

All sensitivity analyses were presented under the outcome.

Assessment of reporting biases

Since there was no meaningful way in which to rank these studies (i.e. there was no specific change in the risk of bias in the studies, sample size, or the control group used over time), we were unable to perform the comparison‐adjusted funnel plot. However, important outcomes such as all‐cause mortality and adverse events were not reported in some trials indicating the possibility of reporting biases.

Discusión

disponible en

Resumen de los resultados principales

Se realizó una revisión sistemática y un metanálisis en red de todos los tratamientos disponibles para la ascitis en pacientes con cirrosis hepática descompensada. Esta revisión incluyó 49 ensayos con 3521 participantes. En estos ensayos se compararon un total de 21 intervenciones. Se incluyó un total de 42 ensayos que incluyeron 2870 participantes en uno o más resultados de esta revisión (Gregory 1977; Fogel 1981; Descos 1983; Gines 1987; Salerno 1987; Chesta 1990; Ginès 1991; Strauss 1991; Acharya 1992; Hagege 1992; Ljubici 1994; Sola 1994; Ginès 1995; Schaub 1995; Lebrec 1996; Fernandez‐Esparrach 1997; Graziotto 1997; Mehta 1998; Gentilini 1999a; Rossle 2000; Ginès 2002; Moreau 2002; Sanyal 2003; Salerno 2004; Romanelli 2006; Singh 2006a; Singh 2006b; Lata 2007; Singh 2008; Licata 2009; Narahara 2011; Raza 2011; Bari 2012; Singh 2012a; Singh 2013; Ali 2014; Hamdy 2014; Tuttolomondo 2016; Bureau 2017c; Rai 2017; Caraceni 2018; Sola 2018).

En general, el 36,8% de los participantes del ensayo que recibieron el tratamiento estándar de paracentesis más reposición de líquidos murieron durante el período de seguimiento, que varió entre una semana y 11 meses. No se encontró evidencia de diferencias en la mortalidad ni en los efectos adversos graves en ninguna de las comparaciones directas ni en el metanálisis en red. Sin embargo, los intervalos de confianza fueron amplios y no se pueden descartar diferencias clínicamente importantes en cuanto a la mortalidad o los efectos adversos graves.

La calidad de vida relacionada con la salud se informó solo en un ensayo que comparó antagonistas de la aldosterona más diuréticos de asa más albúmina versus antagonistas de la aldosterona más diuréticos de asa más paracentesis más reemplazo de líquidos. La diferencia de medias fue 0,06. Se desconoce la diferencia mínima clínicamente importante para el EQ‐5D en los pacientes con cirrosis. En otras afecciones, una diferencia de 0,04 a 0,20 es clínicamente importante (Asher 2018; Sims 2018; Hoehle 2019; Kato 2019). Por lo tanto, no está claro si la diferencia de 0,06 con los antagonistas de la aldosterona más diuréticos de asa más albúmina y los antagonistas de la aldosterona más diuréticos de asa más paracentesis más reemplazo de líquidos es clínicamente importante. También hay que señalar que no hay información sobre si esta diferencia fue reproducible, ya que este fue el único ensayo en esta comparación. Por lo tanto, hay una considerable incertidumbre sobre la diferencia entre los grupos.

Hubo diferencias entre los distintos grupos en "cualquier" evento adverso, pero ninguna de las comparaciones en las que hubo diferencias se pudo considerar como "estándar de atención"; por lo tanto, las implicaciones de estos hallazgos no son clínicamente relevantes. La resolución de la ascitis fue mayor con la derivación portosistémica intrahepática transyugular versus la paracentesis más reemplazo de líquidos. Aunque la resolución de la ascitis fue mayor al añadir antagonistas de aldosterona a la paracentesis más reposición de líquidos, este resultado se basó en un único ensayo pequeño de alto riesgo de sesgo (tamaño de la muestra: 36 participantes), lo que indica que existe una gran incertidumbre sobre esta cuestión.

El número de otros eventos de descompensación y la duración de la estancia hospitalaria fueron mayores con los antagonistas de la aldosterona más diuréticos de asa versus paracentesis más reemplazo de líquidos. En el metanálisis en red, varios otros tratamientos, incluida la derivación portosistémica intrahepática transyugular, tuvieron menos eventos de descompensación y una menor duración de la estancia hospitalaria que los antagonistas de la aldosterona más los diuréticos de asa sin paracentesis. Por lo tanto, los antagonistas de la aldosterona más los diuréticos de asa sin paracentesis parecen ser los peores entre los tratamientos habituales comparados en esta revisión.

Los costes del tratamiento con paracentesis más vasoconstrictores sistémicos fueron inferiores a los de la paracentesis más reposición de líquidos en los tres ensayos que proporcionaron esta información, aunque la variación entre los estudios fue muy grande y no se realizó un metanálisis. Además, en presencia de una considerable incertidumbre en cuanto a los efectos beneficiosos y perjudiciales de los diferentes tratamientos, los costes del tratamiento no pueden determinar por sí solos si una intervención es mejor que otra.

La mediana ponderada de la mortalidad en el grupo de paracentesis más reposición de líquidos fue del 36,8% en 11 meses. El tamaño de la muestra necesario para detectar una reducción del riesgo relativo del 20% en el grupo experimental, con un error tipo I del 5% y un error tipo II del 20%, es de 1282 participantes. Aunque aproximadamente el 20% de los pacientes con cirrosis hepática desarrollan ascitis, la mayoría puede ser grado 2 y pueden ser susceptibles al tratamiento con diuréticos. Sin embargo, una proporción significativa puede ser grado 3, refractaria o recurrente. Hay poca información sobre la incidencia o prevalencia de la ascitis refractaria o recurrente grado 3. En un pequeño estudio realizado en Túnez se calculó que alrededor del 20% de todos los ingresos hospitalarios de pacientes con cirrosis se debían a la ascitis refractaria (Ennaifer 2014). Si incluso el 5% de los ingresos hospitalarios por cirrosis hepática se relacionan con ascitis refractaria grado 3 o recurrente en el Reino Unido, un ensayo como el estipulado es muy factible.

Hubo aproximadamente otros 44 eventos de descompensación por cada 100 participantes del grupo de paracentesis más reposición de líquidos. Además de causar la muerte, la descompensación suele dar lugar a ingresos hospitalarios y a costes significativos para el servicio de salud. Por lo tanto, "cualquier evento de descompensación" es otro posible resultado primario. Si se supone que la varianza fuera igual a la media en una distribución de Poisson ordinaria utilizada con frecuencia para analizar los eventos recurrentes (que ocurren independientemente, aunque esta es una suposición cuestionable), para una reducción del riesgo relativo del 20% en el grupo experimental, con un error tipo I del 5% y un error tipo II del 20%, el tamaño de la muestra requerida en un ensayo que utilice cualquier evento de descompensación es de 786 participantes.

En cuanto a las intervenciones que se compararán en ensayos futuros, la paracentesis más el reemplazo de líquidos fue la intervención más frecuente en esta revisión. Por lo tanto, se debería considerar como una de las intervenciones de los ensayos futuros. Los antagonistas de la aldosterona más diuréticos de asa en lugar de la paracentesis más la reposición de líquidos parecen aumentar los otros eventos de descompensación y la duración de la estancia hospitalaria (y la paracentesis o la TIPS pueden ser necesarias en pacientes que no responden a los diuréticos), aunque esto se basa en ensayos con alto riesgo de sesgo. Sin embargo, añadir diuréticos a la paracentesis más reposición de líquidos es una de las opciones de intervención (en particular, porque en la actualidad es el tratamiento recomendado por la AASLD y la EASL, aunque no hay evidencia para considerarla superior a la paracentesis más reposición de líquidos solamente); la derivación portosistémica intrahepática transyugular puede ser otra opción. Esas derivaciones pueden ser eficaces para prevenir nuevas hemorragia de las várices (Qi 2016), pero pueden aumentar la encefalopatía hepática (Saab 2006; Zhou 2019). Por lo tanto, el impacto de los eventos de descompensación en la calidad de vida y la capacidad de realizar las actividades cotidianas, sociales y laborales se debe evaluar como parte de los ensayos futuros.

Compleción y aplicabilidad general de las pruebas

No pareció haber restricciones sobre la base de la etiología o la presencia de otras características de descompensación en los ensayos que proporcionaron esta información. Por lo tanto, los resultados de los estudios son aplicables a los pacientes con cirrosis resultante de diversas etiologías que presentan ascitis. Sin embargo, parece que los ensayos incluyeron principalmente a pacientes con ascitis grado 3, refractaria o recurrente. Por lo tanto, las conclusiones de esta revisión sólo son aplicables a estos pacientes. En la actualidad no hay información sobre qué diurético es mejor para los pacientes con cirrosis y ascitis grado 2 que no sea refractaria o recurrente. Por lo tanto, se necesitan ensayos clínicos aleatorizados factibles que examinen los posibles efectos de los diferentes diuréticos. La incidencia de ascitis grado 3, recurrente o refractaria puede ser un resultado adecuado para tales ensayos.

Además, 38 ensayos excluyeron a los participantes con otras características de descompensación activas como la hemorragia activa de las várices, el síndrome hepatorrenal y la encefalopatía hepática grado III o grado IV, mientras que los 11 ensayos restantes no informaron si incluyeron a algún participante con otras características de descompensación activas. Por lo tanto, los resultados de la revisión sólo son aplicables a los pacientes sin otros eventos de descompensación activos. Por lo tanto, parece que se necesita más evidencia sobre el tratamiento de la ascitis en poblaciones con ascitis y otros signos de descompensación.

Calidad de la evidencia

Sin embargo, la certeza (calidad) general de la evidencia fue muy baja. Una de las principales razones de la escasa certeza de la evidencia fue el riesgo incierto o alto de sesgo en todos los ensayos. Es posible realizar ensayos con bajo riesgo de sesgo en ciertas comparaciones: la asignación al azar se puede realizar mediante métodos estándar, por ejemplo, asignación al azar central por Internet; se puede realizar un análisis por intención de tratar; y se debe publicar un protocolo antes del reclutamiento. Sin embargo, el cegamiento de los profesionales sanitarios y los participantes puede no ser posible si se utiliza la TIPS como una de las intervenciones. Con una planificación cuidadosa es posible lograr el cegamiento para otras comparaciones, por ejemplo, con el uso de placebo para los diuréticos si el ensayo consiste en añadir diuréticos a la paracentesis más reemplazo de líquidos. El cegamiento del evaluador de resultados se puede lograr en todas las comparaciones.

Otra razón importante de la muy baja certeza de la evidencia fue la imprecisión: los ensayos tenían tamaños de la muestra pequeños y los intervalos de confianza se superponían para los efectos beneficiosos y perjudiciales clínicamente significativos en la mayoría de las comparaciones. Por lo tanto, los ensayos futuros deberán tener un poder estadístico adecuado con tamaños de la muestra como se ha descrito anteriormente.

Se utilizaron los resultados clínicos; por lo tanto, no hay problemas de falta de direccionalidad debido a los resultados. No se indicó que los posibles modificadores del efecto fueran sistemáticamente diferentes en las comparaciones (es decir, no hubo preocupación por la suposición de transitividad). Aunque hubo evidencia de inconsistencia según el ajuste del modelo, inconsistencia en los gráficos de factores y varianza entre los diseños, el análisis de un subgrupo de participantes con ascitis grado 3 (cuando fue posible) no dio lugar a grandes diferencias en la interpretación de los resultados. Del mismo modo, el análisis de un subgrupo de participantes con ascitis refractaria o recurrente (cuando fue posible) no dio lugar a grandes diferencias en la interpretación de las conclusiones. Sin embargo, no se puede descartar inconsistencia ("incoherencia" según la terminología GRADE).

Estos estudios no se pudieron clasificar de forma adecuada (es decir, no hubo cambios específicos en el riesgo de sesgo de los estudios, el tamaño de la muestra ni el grupo control utilizado con el tiempo); se ha completado una búsqueda exhaustiva de estudios sobre la eficacia. Sin embargo, se incluyeron diferentes grupos de ensayos para diferentes resultados: sólo entre el 30% y el 70% de los ensayos informaron sobre la mortalidad, los eventos adversos graves, el trasplante de hígado, la resolución de la ascitis y otros eventos de descompensación, aunque estos resultados se hubieran medido de forma habitual en ensayos de esta naturaleza. Esto puede indicar un sesgo de informe en estos resultados.

Sesgos potenciales en el proceso de revisión

Para la búsqueda se seleccionó una variedad de bases de datos sin restricciones de idioma y el metanálisis en red se realizó según la guía NICE DSU. Además, el análisis se realizó con el uso del modelo de efectos fijos y el modelo de efectos aleatorios y las inconsistencias se evaluaron y comunicaron siempre que fue posible. Estas son fortalezas del proceso de revisión.

Se excluyeron los estudios que compararon las variaciones en la duración o la dosis en las diferentes intervenciones. Por lo tanto, esta revisión no proporciona información sobre si una variación es mejor que otra. Otra limitación importante de esta revisión fue la escasez de datos: los ensayos fueron pequeños. Esta escasez de datos disminuye la confianza en los resultados.

Todos los metanálisis en red incluyeron sólo datos escasos de los ensayos, la mayoría de los cuales tenían un alto riesgo de sesgo. Sin embargo, los posibles modificadores de los efectos en los ensayos que los informaron fueron muy similares en todas las comparaciones. Los resultados de las comparaciones directas e indirectas fueron similares para la mayoría de los resultados en los que se pudo evaluar. Por lo tanto, la preocupación sobre la suposición de transitividad fue escasa. Sin embargo, no se puede descartar.

Solo se incluyeron ensayos clínicos aleatorizados, que se sabe que se centran principalmente en los efectos beneficiosos y no recopilan ni informan los efectos perjudiciales de manera detallada. Se requirió un esfuerzo significativo para identificar estudios no aleatorizados que informaran sobre los efectos perjudiciales. También fue difícil evaluar el riesgo de sesgo en esos estudios. Si los futuros ensayos clínicos aleatorizados se basan en la mortalidad u otros eventos de descompensación, probablemente no sea necesario realizar una revisión sistemática de los eventos adversos a partir de estudios observacionales.

Acuerdos y desacuerdos con otros estudios o revisiones

Este es el primer metanálisis en red sobre el tema. Se han realizado varias revisiones sistemáticas y comparaciones directas de diferentes intervenciones para el tratamiento de los pacientes con cirrosis y ascitis.

Guo y colegas evaluaron el papel de la midodrina en pacientes con cirrosis y ascitis (Guo 2016). No encontraron efectos beneficiosos de la midodrina en términos de resultados clínicos a pesar de que hubo una mejoría en resultados alternativos como las tasas de respuesta y la actividad de la renina plasmática (Guo 2016). También encontraron que la midodrina podría ser potencialmente perjudicial cuando se utiliza como sustituta para el reemplazo de líquidos después de la paracentesis (Guo 2016). En la presente revisión no se encontró evidencia de efectos beneficiosos o perjudicial de los vasoconstrictores sistémicos en pacientes con ascitis y cirrosis. Lo anterior se puede deber a los diferentes métodos utilizados para el metanálisis: en la presente revisión se consideró que cointervenciones como los diuréticos o los vasodilatadores utilizados podrían influir en el efecto de los vasoconstrictores sistémicos y se han considerado como "nodos" diferentes en el metanálisis en red, mientras que Guo y colegas combinaron los ensayos a pesar de las diferencias en los diuréticos o vasodilatadores utilizados. El método utilizado para el metanálisis (método bayesiano versus frecuentista) podría ser una razón adicional para la diferencia.

Simonetti y colegas evaluaron el papel de los diferentes líquidos después de la paracentesis y no encontraron una evidencia de diferencia en los resultados entre los diferentes líquidos utilizados después de la paracentesis, incluyendo la reinfusión del líquido ascítico (Simonetti 2019). Aunque en esta revisión no se pueden hacer comentarios sobre los diferentes líquidos después de la paracentesis, ya que no se exploró este tema, se coincide en que no hay evidencia de diferencias entre la paracentesis más la reinfusión y la paracentesis más el reemplazo de líquidos.

Saab y colegas determinaron que la TIPS era más eficaz en la resolución de la ascitis que la paracentesis y la reposición de líquidos, pero encontraron que la incidencia de encefalopatía hepática era mayor (Saab 2006). Sin embargo, no encontraron evidencia de diferencias en otros eventos de descompensación. El metanálisis en red de la presente revisión también demostró que la TIPS pueden ser más efectiva en la resolución de la ascitis que la paracentesis más el reemplazo de líquidos. Los eventos individuales de descompensación no se analizaron por separado. Por lo tanto, no se pueden hacer comentarios sobre si la encefalopatía hepática aumentó con la TIPS en comparación con la paracentesis más el reemplazo de líquidos.

A high resolution version of this image can be found at: https://doi.org/10.5281/zenodo.3604788..The network plots showing the outcomes for which network meta‐analysis was performed. The size of the node (circle) provides a measure of the number of trials in which the particular Intervention was included as one of the intervention groups. The thickness of the line provides a measure of the number of direct comparisons between two nodes (Interventions). A higher resolution image of this picture is available at: http://doi.org/10.5281/zenodo.3531818.Abbreviations Alb = Albumin
 AldoAnt = Aldosterone antagonists
 Fluid = Fluid replacement
 LoopD = Loop diuretics
 No active treatment = No active treatment
 OsmoD = Osmotic diuretics
 Paracen = Paracentesis
 PVShunt = Peritoneovenous shunt
 Reinf = Reinfusion
 Vasocons = Systemic vasoconstrictors
 Vasodil = Systemic vasodilator
 ThiazD = Thiazide diuretics
 TIPS = Transjugular intrahepatic portosystemic shunt
Figuras y tablas -
Figure 1

A high resolution version of this image can be found at: https://doi.org/10.5281/zenodo.3604788..

The network plots showing the outcomes for which network meta‐analysis was performed. The size of the node (circle) provides a measure of the number of trials in which the particular Intervention was included as one of the intervention groups. The thickness of the line provides a measure of the number of direct comparisons between two nodes (Interventions). A higher resolution image of this picture is available at: http://doi.org/10.5281/zenodo.3531818.

Abbreviations

Alb = Albumin
AldoAnt = Aldosterone antagonists
Fluid = Fluid replacement
LoopD = Loop diuretics
No active treatment = No active treatment
OsmoD = Osmotic diuretics
Paracen = Paracentesis
PVShunt = Peritoneovenous shunt
Reinf = Reinfusion
Vasocons = Systemic vasoconstrictors
Vasodil = Systemic vasodilator
ThiazD = Thiazide diuretics
TIPS = Transjugular intrahepatic portosystemic shunt

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Study flow diagram.
Figuras y tablas -
Figure 2

Study flow diagram.

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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Figure 4

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Inconsistency factor plots showing the inconsistency factors for the outcomes with direct and indirect evidence available for one or more comparisons. There was no evidence of inconsistency except for hospital stay. A higher resolution image of this picture is available at: http://doi.org/10.5281/zenodo.3531818.Abbreviations: Alb = Albumin
 AldoAnt = Aldosterone antagonists
 Fluid = Fluid replacement
 LoopD = Loop diuretics
 No active treatment = No active treatment
 OsmoD = Osmotic diuretics
 Paracen = Paracentesis
 PVShunt = Peritoneovenous shunt
 Reinf = Reinfusion
 Vasocons = Systemic vasoconstrictors
 Vasodil = Systemic vasodilator
 ThiazD = Thiazide diuretics
 TIPS = Transjugular intrahepatic portosystemic shunt
Figuras y tablas -
Figure 5

Inconsistency factor plots showing the inconsistency factors for the outcomes with direct and indirect evidence available for one or more comparisons. There was no evidence of inconsistency except for hospital stay. A higher resolution image of this picture is available at: http://doi.org/10.5281/zenodo.3531818.

Abbreviations:

Alb = Albumin
AldoAnt = Aldosterone antagonists
Fluid = Fluid replacement
LoopD = Loop diuretics
No active treatment = No active treatment
OsmoD = Osmotic diuretics
Paracen = Paracentesis
PVShunt = Peritoneovenous shunt
Reinf = Reinfusion
Vasocons = Systemic vasoconstrictors
Vasodil = Systemic vasodilator
ThiazD = Thiazide diuretics
TIPS = Transjugular intrahepatic portosystemic shunt

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Forest plots showing the outcomes for which the random‐effects model were different from the fixed‐effect model. The more conservative random‐effects model was used. In this figure, mortality at maximal follow‐up, any adverse events (number of people), and resolution of ascites are shown. shows the remaining outcomes (other decompensation events and length of hospital stay), the other outcomes in which the fixed‐effect and random‐effects model were different. A higher resolution image of this picture is available at: http://doi.org/10.5281/zenodo.3531818.Abbreviations: Alb = Albumin
 AldoAnt = Aldosterone antagonists
 Fluid = Fluid replacement
 LoopD = Loop diuretics
 No active treatment = No active treatment
 OsmoD = Osmotic diuretics
 Paracen = Paracentesis
 PVShunt = Peritoneovenous shunt
 Reinf = Reinfusion
 Vasocons = Systemic vasoconstrictors
 Vasodil = Systemic vasodilator
 ThiazD = Thiazide diuretics
 TIPS = Transjugular intrahepatic portosystemic shunt
Figuras y tablas -
Figure 6

Forest plots showing the outcomes for which the random‐effects model were different from the fixed‐effect model. The more conservative random‐effects model was used. In this figure, mortality at maximal follow‐up, any adverse events (number of people), and resolution of ascites are shown. Figure 7 shows the remaining outcomes (other decompensation events and length of hospital stay), the other outcomes in which the fixed‐effect and random‐effects model were different. A higher resolution image of this picture is available at: http://doi.org/10.5281/zenodo.3531818.

Abbreviations:

Alb = Albumin
AldoAnt = Aldosterone antagonists
Fluid = Fluid replacement
LoopD = Loop diuretics
No active treatment = No active treatment
OsmoD = Osmotic diuretics
Paracen = Paracentesis
PVShunt = Peritoneovenous shunt
Reinf = Reinfusion
Vasocons = Systemic vasoconstrictors
Vasodil = Systemic vasodilator
ThiazD = Thiazide diuretics
TIPS = Transjugular intrahepatic portosystemic shunt

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Forest plots showing the outcomes for which the random‐effects model were different from the fixed‐effect model. The more conservative random‐effects model was used. In this figure, other decompensation events and length of hospital stay are shown. shows the remaining outcomes (mortality at maximal follow‐up, any adverse events (number of people), and resolution of ascites), the other outcomes in which the fixed‐effect and random‐effects model were different. A higher resolution image of this picture is available at: http://doi.org/10.5281/zenodo.3531818.Abbreviations: Alb = Albumin
 AldoAnt = Aldosterone antagonists
 Fluid = Fluid replacement
 LoopD = Loop diuretics
 No active treatment = No active treatment
 OsmoD = Osmotic diuretics
 Paracen = Paracentesis
 PVShunt = Peritoneovenous shunt
 Reinf = Reinfusion
 Vasocons = Systemic vasoconstrictors
 Vasodil = Systemic vasodilator
 ThiazD = Thiazide diuretics
 TIPS = Transjugular intrahepatic portosystemic shunt
Figuras y tablas -
Figure 7

Forest plots showing the outcomes for which the random‐effects model were different from the fixed‐effect model. The more conservative random‐effects model was used. In this figure, other decompensation events and length of hospital stay are shown. Figure 6 shows the remaining outcomes (mortality at maximal follow‐up, any adverse events (number of people), and resolution of ascites), the other outcomes in which the fixed‐effect and random‐effects model were different. A higher resolution image of this picture is available at: http://doi.org/10.5281/zenodo.3531818.

Abbreviations:

Alb = Albumin
AldoAnt = Aldosterone antagonists
Fluid = Fluid replacement
LoopD = Loop diuretics
No active treatment = No active treatment
OsmoD = Osmotic diuretics
Paracen = Paracentesis
PVShunt = Peritoneovenous shunt
Reinf = Reinfusion
Vasocons = Systemic vasoconstrictors
Vasodil = Systemic vasodilator
ThiazD = Thiazide diuretics
TIPS = Transjugular intrahepatic portosystemic shunt

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Treatment for ascites in people with decompensated liver cirrhosis

Patient or population: people with liver cirrhosis and ascites
Settings: secondary or tertiary care
Intervention: various interventions
Comparison: paracentesis plus fluid replacement
Follow‐up period: 0.1 to 84 months
Network geometry plots:Figure 1

Outcomes

Aldosterone antagonists plus loop diuretics

Paracentesis plus systemic vasoconstrictors

Aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement

Transjugular intrahepatic portosystemic shunt

Mortality at maximal follow‐up

Paracentesis plus fluid replacement
368 per 1000
(36.8%)

HR 1.05
(0.70 to 1.69)
Network estimate

18 more per 1000
(109 fewer to 253 more)

HR 1.64
(0.46 to 6.32)
Network estimate

235 more per 1000
(200 fewer to 632 more)

HR 1.24
(0.62 to 2.59)
Network estimate

88 more per 1000
(141 fewer to 587 more)

HR 0.84
(0.60 to 1.18)
Network estimate

59 fewer per 1000
(148 fewer to 65 more)

Very low1,2,3

Very low1,2,3

Very low1,2,3

Very low1,2,3

Based on 211 participants (4 RCTs)

Based on 165 participants (5 RCTs)

No direct RCT

Based on 452 participants (7 RCTs)

Serious adverse events (number of events)

Paracentesis plus fluid replacement
0 per 1000
(0 per 100 participants)

Rate ratio 1.30
(0.27 to 6.99)
Direct estimate

Not estimable

‐

‐

Not estimable

(10 serious adverse events in 35 participants)

Very low1,2,3

Very low1,2,3

Based on 41 participants (1 RCT)

Based on 70 participants (1 RCT)

Any adverse events (number of people)

Paracentesis plus fluid replacement
100 per 1000
(10%)

OR 3.54
(0.43 to 27.41)
Network estimate

182 more per 1000
(54 fewer to 653 more)

OR 1.63
(0.30 to 11.66)
Network estimate

53 more per 1000
(68 fewer to 464 more)

‐

‐

Very low1,2,3

Very low1,2,3

Based on 84 participants (2 RCTs)

Based on 145 participants (4 RCTs)

Any adverse events (number of events)

Paracentesis plus fluid replacement
118 per 1000
(11.8 per 100 participants)

Rate ratio 4.12
(0.87 to 34.02)
Network estimate

367 more per 1000
(15 fewer to 3885 more)

Rate ratio 1.37
(0.36 to 5.82)
Network estimate

43 more per 1000
(76 fewer to 567 more)

‐

‐

Very low1,2,3

Very low1,2,3

Based on 31 participants (1 RCT)

Based on 25 participants (1 RCT)

Liver transplantation at maximal follow‐up

Paracentesis plus fluid replacement
121 per 1000
(12.1%)

‐

HR 1.08
(0.11 to 10.35)
Network estimate

10 more per 1000
(108 fewer to 879 more)

‐

HR 0.87
(0.52 to 1.44)
Network estimate

15 fewer per 1000
(58 fewer to 54 more)

Very low1,2,3

Very low1,2,3

Based on 145 participants (4 RCTs)

Based on 427 participants (6 RCT)

Resolution of ascites at maximal follow‐up (by ultrasound)

Paracentesis plus fluid replacement
158 per 1000
(15.8%)

HR 1.10
(0.12 to 10.74)
Network estimate

16 more per 1000
(140 fewer to 842 more)

‐

HR 1.17
(0.01 to 98.79)
Network estimate

27 more per 1000
(156 fewer to 842 more)

HR 9.44
(1.93 to 62.68)
Network estimate

842 more per 1000
(147 more to 842 more)

Very low1,2,3,4

Very low1,2,3,4

Very low1,2,4

Based on 125 participants (3 RCTs)

No direct RCT

Based on 392 participants (6 RCTs)

Other features of decompensation at maximal follow‐up

Paracentesis plus fluid replacement
439 per 1000
(43.9 per 100 participants)

Rate ratio 2.04
(1.37 to 3.10)
Network estimate

458 more per 1000
(164 more to 922 more)

Rate ratio 0.76
(0.14 to 3.61)
Network estimate

107 fewer per 1000
(377 fewer to 1144 more)

Rate ratio 1.04
(0.56 to 1.93)
Network estimate

16 more per 1000
(195 fewer to 409 more)

Rate ratio 1.17
(0.92 to 1.49)
Network estimate

76 more per 1000
(33 fewer to 217 more)

Very low1,2,4

Very low1,2,3,4

Very low1,2,3,4

Very low1,2,3,4

Based on 242 participants (4 RCTs)

Based on 114 participants (3 RCTs)

No direct RCT

Based on 452 participants (7 RCTs)

*Ranking was not provided because of the considerable uncertainty in the ranking.
CrI: Credible interval; OR: Odds Ratio; HR: Hazard Ratio.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

1Downgraded one level for risk of bias because the trial(s) included in the analysis was/were at high risk of bias
2Downgraded one level for imprecision because the sample size was small
3Downgraded one level for imprecision because the credible intervals were wide (included clinical benefit and harms)
4Downgraded one level for inconsistency because there was evidence of statistical heterogeneity

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Treatment for ascites in people with decompensated liver cirrhosis

Patient or population: people with liver cirrhosis and ascites
Settings: secondary or tertiary care
Intervention: various interventions
Comparison: paracentesis plus fluid replacement
Follow‐up period: 0.1 to 84 months
Network geometry plots:Figure 1

Interventions

Relative effect
(95% CrI)

Anticipated absolute effect* (95% CrI)

Quality of evidence

Paracentesis plus fluid replacement

Various interventions

Difference

Mortality at maximal follow‐up
Total studies: 32
Total participants: 2448

Paracentesis plus fluid replacement

Reference

Aldosterone antagonists plus loop diuretics
(4 RCTs; 211 participants)

HR 1.05
(0.70 to 1.69)
Network estimate

368 per 1000

387 per 1000
(260 to 621)

18 more per 1000
(109 fewer to 253 more)

Very low1,2,3

Paracentesis plus systemic vasoconstrictors
(5 RCTs; 165 participants)

HR 1.64
(0.46 to 6.32)
Network estimate

368 per 1000

604 per 1000
(168 to 1000)

235 more per 1000
(200 fewer to 632 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement
(No direct RCT)

HR 1.24
(0.62 to 2.59)
Network estimate

368 per 1000

457 per 1000
(227 to 955)

88 more per 1000
(141 fewer to 587 more)

Very low1,2,3

Transjugular intrahepatic portosystemic shunt
(7 RCTs; 452 participants)

HR 0.84
(0.60 to 1.18)
Network estimate

368 per 1000

309 per 1000
(221 to 433)

59 fewer per 1000
(148 fewer to 65 more)

Very low1,2,3

No active treatment
(No direct RCT)

HR 1.66
(0.46 to 6.99)
Network estimate

368 per 1000

611 per 1000
(170 to 1000)

243 more per 1000
(199 fewer to 632 more)

Very low1,2,3

Loop diuretics
(No direct RCT)

HR 0.71
(0.23 to 2.16)
Network estimate

368 per 1000

263 per 1000
(84 to 797)

105 fewer per 1000
(284 fewer to 429 more)

Very low1,2,3

Paracentesis plus reinfusion
(1 RCT; 24 participants)

HR 0.77
(0.23 to 2.68)
Network estimate

368 per 1000

284 per 1000
(84 to 987)

84 fewer per 1000
(285 fewer to 619 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus albumin
(No direct RCT)

HR 1.06
(0.57 to 2.16)
Network estimate

368 per 1000

392 per 1000
(209 to 795)

23 more per 1000
(159 fewer to 427 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus peritoneovenous shunt
(No direct RCT)

HR 0.97
(0.40 to 2.43)
Network estimate

368 per 1000

358 per 1000
(148 to 894)

10 fewer per 1000
(221 fewer to 526 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors
(No direct RCT)

HR 0.42
(0.15 to 1.22)
Network estimate

368 per 1000

153 per 1000
(55 to 450)

215 fewer per 1000
(313 fewer to 82 more)

Very low1,2,3

Aldosterone antagonists
(No direct RCT)

HR 1.92
(0.24 to 20.64)
Network estimate

368 per 1000

708 per 1000
(90 to 1000)

340 more per 1000
(278 fewer to 632 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus paracentesis plus fluid replacement
(No direct RCT)

HR 1.11
(0.02 to 39.77)
Network estimate

368 per 1000

408 per 1000
(9 to 1000)

40 more per 1000
(360 fewer to 632 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus systemic vasodilator
(No direct RCT)

HR 0.61
(0.02 to 9.17)
Network estimate

368 per 1000

226 per 1000
(9 to 1000)

142 fewer per 1000
(360 fewer to 632 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus systemic vasodilator
(No direct RCT)

HR 0.62
(0.03 to 9.10)
Network estimate

368 per 1000

228 per 1000
(12 to 1000)

140 fewer per 1000
(357 fewer to 632 more)

Very low1,2,3

Systemic vasoconstrictors plus albumin
(No direct RCT)

HR 2.62
(0.41 to 19.28)
Network estimate

368 per 1000

965 per 1000
(151 to 1000)

596 more per 1000
(218 fewer to 632 more)

Very low1,2,3

Serious adverse events (number of people)

None of the trials with paracentesis plus fluid replacement as an intervention reported this outcome

Serious adverse events (number of events)
Total studies: 1
Total participants: 41

Paracentesis plus fluid replacement

Reference

Aldosterone antagonists plus loop diuretics
(1 RCT; 41 participants)

Rate ratio 1.30
(0.27 to 6.99)
Direct estimate

0 per 1000

Not estimable

Very low1,2,3

Transjugular intrahepatic portosystemic shunt

(1 RCT; 70 participants)

Not estimable

(10 serious adverse events in 35 participants)

0 per 1000

Not estimable

Very low1,2,3

Health‐related quality of life

None of the trials with paracentesis plus fluid replacement as an intervention reported this outcome

Any adverse events (number of people)
Total studies: 6
Total participants: 229

Paracentesis plus fluid replacement

Reference

Paracentesis plus systemic vasoconstrictors
(4 RCTs; 145 participants)

OR 1.63
(0.30 to 11.66)
Network estimate

100 per 1000

153 per 1000
(32 to 564)

53 more per 1000
(68 fewer to 464 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics
(2 RCT; 84 participants)

OR 3.54
(0.43 to 27.41)
Network estimate

100 per 1000

282 per 1000
(46 to 753)

182 more per 1000
(54 fewer to 653 more)

Very low1,2,3

Any adverse events (number of events)
Total studies: 3
Total participants: 116

Paracentesis plus fluid replacement

Reference

Aldosterone antagonists plus loop diuretics
(1 RCT; 31 participants)

Rate ratio 4.12
(0.87 to 34.02)
Network estimate

118 per 1000

485 per 1000
(103 to 4003)

367 more per 1000
(15 fewer to 3885 more)

Very low1,2,3

Paracentesis plus systemic vasoconstrictors
(1 RCT; 25 participants)

Rate ratio 1.37
(0.36 to 5.82)
Network estimate

118 per 1000

161 per 1000
(42 to 685)

43 more per 1000
(76 fewer to 567 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors
(No direct RCT)

Rate ratio 3.30
(0.38 to 38.51)
Network estimate

118 per 1000

388 per 1000
(45 to 4531)

271 more per 1000
(73 fewer to 4413 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus systemic vasodilator
(No direct RCT)

Rate ratio 4.25
(0.53 to 46.99)
Network estimate

118 per 1000

501 per 1000
(62 to 5529)

383 more per 1000
(55 fewer to 5411 more)

Very low1,2,3

Aldosterone antagonists plus loop diuretics plus systemic vasodilator
(No direct RCT)

Rate ratio 2.41
(0.24 to 29.67)
Network estimate

118 per 1000

284 per 1000
(28 to 3490)

166 more per 1000
(89 fewer to 3372 more)

Very low1,2,3

Liver transplantation at maximal follow‐up
Total studies: 11
Total participants: 596

Paracentesis plus fluid replacement

Reference

Paracentesis plus systemic vasoconstrictors
(4 RCTs; 145 participants)

HR 1.08
(0.11 to 10.35)
Network estimate

121 per 1000

131 per 1000
(14 to 1000)

10 more per 1000
(108 fewer to 879 more)

Very low1,2,3

Transjugular intrahepatic portosystemic shunt
(6 RCTs; 427 participants)

HR 0.87
(0.52 to 1.44)
Network estimate

121 per 1000

106 per 1000
(63 to 175)

15 fewer per 1000
(58 fewer to 54 more)

Very low1,2,3

Paracentesis plus reinfusion
(1 RCT; 24 participants)

HR 2.56
(0.20 to 90.92)
Network estimate

121 per 1000

310 per 1000
(25 to 1000)

189 more per 1000
(97 fewer to 879 more)

Very low1,2,3

Symptomatic resolution of ascites at maximal follow‐up

None of the trials reported this outcome

Resolution of ascites at maximal follow‐up (by ultrasound)
Total studies: 17
Total participants: 1007

Paracentesis plus fluid replacement

Reference

Aldosterone antagonists plus loop diuretics
(3 RCTs; 125 participants)

HR 1.10
(0.12 to 10.74)
Network estimate

158 per 1000

174 per 1000
(18 to 1000)

16 more per 1000
(140 fewer to 842 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement
(No direct RCT)

HR 1.17
(0.01 to 98.79)
Network estimate

158 per 1000

185 per 1000
(2 to 1000)

27 more per 1000
(156 fewer to 842 more)

Very low1,2,3,4

Transjugular intrahepatic portosystemic shunt
(6 RCTs; 392 participants)

HR 9.44
(1.93 to 62.68)
Network estimate

158 per 1000

1000 per 1000
(305 to 1000)

842 more per 1000
(147 more to 842 more)

Very low1,2,4

No active treatment
(No direct RCT)

HR 0.16
(0.00 to 17.37)
Network estimate

158 per 1000

26 per 1000
(0 to 1000)

132 fewer per 1000
(158 fewer to 842 more)

Very low1,2,3,4

Loop diuretics
(No direct RCT)

HR 2.26
(0.01 to 846.41)
Network estimate

158 per 1000

357 per 1000
(1 to 1000)

199 more per 1000
(157 fewer to 842 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus albumin
(No direct RCT)

HR 3.28
(0.09 to 118.39)
Network estimate

158 per 1000

517 per 1000
(15 to 1000)

360 more per 1000
(143 fewer to 842 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors
(No direct RCT)

HR 8.81
(0.06 to 1908.36)
Network estimate

158 per 1000

1000 per 1000
(10 to 1000)

842 more per 1000
(148 fewer to 842 more)

Very low1,2,3,4

Aldosterone antagonists plus paracentesis plus fluid replacement
(1 RCT; 36 participants)

HR 30.63
(5.06 to 692.98)
Direct estimate

158 per 1000

1000 per 1000
(799 to 1000)

842 more per 1000
(641 more to 842 more)

Low1,2

Other features of decompensation at maximal follow‐up
Total studies: 25
Total participants: 1756

Paracentesis plus fluid replacement

Reference

Aldosterone antagonists plus loop diuretics
(4 RCTs; 242 participants)

Rate ratio 2.04
(1.37 to 3.10)
Network estimate

439 per 1000

896 per 1000
(602 to 1360)

458 more per 1000
(164 more to 922 more)

Very low1,2,4

Paracentesis plus systemic vasoconstrictors
(3 RCTs; 114 participants)

Rate ratio 0.76
(0.14 to 3.61)
Network estimate

439 per 1000

332 per 1000
(62 to 1582)

107 fewer per 1000
(377 fewer to 1144 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus paracentesis plus fluid replacement
(No direct RCT)

Rate ratio 1.04
(0.56 to 1.93)
Network estimate

439 per 1000

455 per 1000
(244 to 848)

16 more per 1000
(195 fewer to 409 more)

Very low1,2,3,4

Transjugular intrahepatic portosystemic shunt
(7 RCTs; 452 participants)

Rate ratio 1.17
(0.92 to 1.49)
Network estimate

439 per 1000

515 per 1000
(405 to 655)

76 more per 1000
(33 fewer to 217 more)

Very low1,2,3,4

No active treatment
(No direct RCT)

Rate ratio 3.34
(0.85 to 13.94)
Network estimate

439 per 1000

1466 per 1000
(374 to 6115)

1028 more per 1000
(64 fewer to 5677 more)

Very low1,2,3,4

Loop diuretics
(No direct RCT)

Rate ratio 0.95
(0.40 to 2.23)
Network estimate

439 per 1000

418 per 1000
(176 to 977)

21 fewer per 1000
(262 fewer to 538 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus albumin
(No direct RCT)

Rate ratio 1.56
(0.84 to 2.87)
Network estimate

439 per 1000

682 per 1000
(369 to 1260)

244 more per 1000
(69 fewer to 821 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus peritoneovenous shunt
(No direct RCT)

Rate ratio 0.84
(0.41 to 1.70)
Network estimate

439 per 1000

369 per 1000
(180 to 747)

70 fewer per 1000
(258 fewer to 308 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors
(No direct RCT)

Rate ratio 0.53
(0.02 to 4.98)
Network estimate

439 per 1000

233 per 1000
(7 to 2185)

205 fewer per 1000
(431 fewer to 1747 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus systemic vasoconstrictors plus systemic vasodilator
(No direct RCT)

Rate ratio 0.53
(0.02 to 4.99)
Network estimate

439 per 1000

233 per 1000
(8 to 2190)

206 fewer per 1000
(431 fewer to 1751 more)

Very low1,2,3,4

Aldosterone antagonists plus loop diuretics plus systemic vasodilator
(No direct RCT)

Rate ratio 0.53
(0.02 to 5.11)
Network estimate

439 per 1000

231 per 1000
(7 to 2241)

208 fewer per 1000
(431 fewer to 1802 more)

Very low1,2,3,4

Systemic vasoconstrictors plus albumin
(No direct RCT)

Rate ratio 3.90
(0.96 to 16.98)
Network estimate

439 per 1000

1712 per 1000
(422 to 7447)

1274 more per 1000
(16 fewer to 7009 more)

Very low1,2,3,4

*Anticipated absolute effect. Anticipated absolute effect compares two risks by calculating the difference between the risks of the intervention group with the weighted median risk of the control group.
**Ranking is not provided because of the considerable uncertainty in the ranking.
CrI: Credible interval; OR: Odds Ratio; HR: Hazard Ratio.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

1Downgraded one level for risk of bias because the trial(s) included in the analysis was/were at high risk of bias
2Downgraded one level for imprecision because the sample size was small
3Downgraded one level for imprecision because the credible intervals were wide (includes clinical benefit and harms)
4Downgraded one level for inconsistency because there was evidence of statistical heterogeneity

Figuras y tablas -
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Table 1. Revised 'International Ascites Club' criteria for refractory ascites

1. Treatment duration: patients must be on intensive diuretic therapy (spironolactone 400 mg/day and furosemide 160 mg/day) for at least 1 week and on a salt‐restricted diet of less than 90 mmol or 5.2 g of salt/day

2. Lack of response: mean weight loss of less than 0.8 kg over 4 days and urinary sodium output less than the sodium intake

3. Early ascites recurrence: reappearance of grade 2 or 3 ascites within 4 weeks of initial mobilisation

4. Diuretic‐induced complications:

  • Diuretic‐induced hepatic encephalopathy is the development of encephalopathy in the absence of any other precipitating factor.

  • Diuretic‐induced renal impairment is an increase of serum creatinine by more than 100% to a value more than 2 mg/dL in patients with ascites responding to treatment.

  • Diuretic‐induced hyponatraemia is defined as a decrease of serum sodium by more than 10 mmol/L to a serum sodium of less than 125 mmol/L.

  • Diuretic induced hypo‐ or hyperkalaemia is defined as a change in serum potassium to less than 3 mmol/L or more than 6 mmol/L despite appropriate measures.

From: Moore 2003.

Figuras y tablas -
Table 1. Revised 'International Ascites Club' criteria for refractory ascites
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Table 2. Characteristics of included studies and potential effect modifiers

This table is too wide to be displayed in RevMan. This table can be found at: https://doi.org/10.5281/zenodo.3604600.

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Table 2. Characteristics of included studies and potential effect modifiers
Ir a la tabla de la revisión
Table 3. Risk of bias

Study name

Sequence generation

Allocation concealment

Blinding of patients and healthcare providers

Blinding of outcome assessors

Missing outcome bias

Selective outcome reporting

Overall risk of bias

Chang 1997

Low

Unclear

Unclear

Unclear

Unclear

Unclear

High

Chesta 1990

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Gines 1987

Low

Unclear

Unclear

Unclear

Unclear

Unclear

High

Hagege 1992

Low

Low

High

High

Unclear

Low

High

Salerno 1987

Unclear

Unclear

Unclear

Unclear

Low

Unclear

High

Schaub 1995

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Al Sebaey 2012

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Appenrodt 2008

Unclear

Unclear

Low

Low

Low

Unclear

High

Bari 2012

Low

Low

Low

Low

Unclear

Unclear

High

Hamdy 2014

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Lata 2007

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Moreau 2002

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Singh 2006a

Low

Low

High

High

Low

Low

High

Singh 2006b

Low

Low

High

High

Unclear

Low

High

Singh 2008

Low

Low

High

High

Low

Low

High

Ljubici 1994

Low

Unclear

Unclear

Unclear

Unclear

Unclear

High

Sola 1994

Low

Unclear

Unclear

Unclear

Unclear

Unclear

High

Strauss 1991

Low

Low

Unclear

Unclear

Unclear

Unclear

High

Bureau 2017c

Low

Unclear

Unclear

Unclear

Low

Unclear

High

Ginès 2002

Unclear

Low

Unclear

Unclear

Low

Unclear

High

Lebrec 1996

Unclear

Low

Unclear

Unclear

Unclear

Unclear

High

Narahara 2011

Low

Low

Unclear

Unclear

Low

Unclear

High

Rossle 2000

Unclear

Unclear

Unclear

Unclear

Low

Unclear

High

Salerno 2004

Unclear

Low

High

High

Low

Unclear

High

Sanyal 2003

Unclear

Low

Unclear

Unclear

Low

Unclear

High

Gregory 1977

Unclear

Unclear

Unclear

Unclear

Low

Unclear

High

Tuttolomondo 2016

Unclear

Unclear

Unclear

Unclear

Low

Unclear

High

Fogel 1981

Unclear

Unclear

High

High

Low

Unclear

High

Licata 2009

Low

Low

Unclear

Unclear

Low

Unclear

High

Bruno 1992

Low

Low

Unclear

Unclear

Low

Unclear

High

Graziotto 1997

Unclear

Low

Unclear

Unclear

Low

Unclear

High

Mehta 1998

Unclear

Unclear

High

High

Unclear

Unclear

High

Gentilini 1999a

Unclear

Unclear

Unclear

Unclear

Low

Unclear

High

Romanelli 2006

Low

Low

Unclear

Unclear

Low

Unclear

High

Caraceni 2018

Low

Low

High

High

Unclear

High

High

Ginès 1991

Low

Unclear

Unclear

Unclear

Unclear

Unclear

High

Ginès 1995

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Singh 2012a

Low

Low

Unclear

Unclear

Low

Low

High

Singh 2013

Low

Low

High

High

Low

Low

High

Fernandez‐Esparrach 1997

Unclear

Unclear

Unclear

Low

Low

Unclear

High

Acharya 1992

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Ali 2014

Low

Low

Low

Low

Unclear

Low

High

Amin 2012

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Descos 1983

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Rai 2017

Low

Low

High

High

Low

Unclear

High

Singh 2013

Low

Low

High

High

Low

Low

High

Singh 2013

Low

Low

High

High

Low

Low

High

Singh 2013

Low

Low

High

High

Low

Low

High

Singh 2013

Low

Low

High

High

Low

Low

High

Singh 2013

Low

Low

High

High

Low

Low

High

Raza 2011

Unclear

Unclear

Low

Low

Unclear

Unclear

High

Stanley 1989b

Unclear

Low

Unclear

Unclear

Low

Unclear

High

Sola 2018

Low

Low

Low

Low

High

Low

High

Mchutchison 1989

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High
Figuras y tablas -
Table 3. Risk of bias
Ir a la tabla de la revisión
Table 4. Model fit

Mortality at maximal follow‐up

Fixed‐effect model

Random‐effects model

Inconsistency model

Dbar

255.1

253.7

255.3

DIC

297.9

299.2

303.1

pD

42.8

45.5

47.75

Any adverse events (number of people)

Fixed‐effect model

Random‐effects model

Inconsistency model

Dbar

38.89

39.75

‐

DIC

46.75

48.72

‐

pD

7.862

8.96

‐

Liver transplantation at maximal follow‐up

Fixed‐effect model

Random‐effects model

Inconsistency model

Dbar

54.83

54.1

‐

DIC

64.51

65.98

‐

pD

9.684

11.88

‐

Resolution of ascites at maximal follow‐up (by ultrasound)

Fixed‐effect model

Random‐effects model

Inconsistency model

Dbar

182.7

135

‐

DIC

206.4

165.3

‐

pD

23.73

30.24

‐

Other features of decompensation at maximal follow‐up

Fixed‐effect model

Random‐effects model

Inconsistency model

Dbar

258

258.1

253

DIC

293.9

294

294.7

pD

35.89

35.92

41.71

Length of hospital stay (days) (all admissions until maximal follow‐up)

Fixed‐effect model

Random‐effects model

Inconsistency model

Dbar

152.7

122.8

122.7

DIC

173.7

147.2

147.3

pD

20.95

24.39

24.56

Treatment costs

Fixed‐effect model

Random‐effects model

Inconsistency model

Dbar

4961

34.09

‐

DIC

4963

38.08

‐

pD

2.023

3.998

‐

Dbar = posterior mean of deviance

DIC = deviance information criteria

pD = effective number of parameters or leverage

Figuras y tablas -
Table 4. Model fit
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Table 5. Effect estimates (network meta‐analysis)

This table is too wide to be displayed in RevMan. This table can be found at: https://doi.org/10.5281/zenodo.3604602

The table provides the effect estimates of each pairwise comparison for the different outcomes. The top half of the table indicates the effect estimates from the direct comparisons. The bottom half of the table indicates the effect estimates from the network meta‐analysis. For network meta‐analysis, to identify the effect estimate of a comparison, say A versus B, look at the cell that occupies the row corresponding to intervention A and the column corresponding to intervention B for the direct effect estimate. If that cell is empty (indicated by a '‐'), look at the row corresponding to intervention B and the column corresponding to intervention A. Take the inverse of this number (i.e. 1/number) to arrive at the treatment effect of A versus B. For direct comparisons, this is exactly the opposite; look at the cell that occupies the column corresponding to intervention A and the row corresponding to intervention B for the direct effect estimate. If that cell is empty, look at the column corresponding to intervention B and the row corresponding to intervention A. Take the inverse of this number to arrive at the treatment effect of A versus B. If the cell corresponding to B versus A is also missing in direct comparisons, this means that there was no direct comparison.

Statistically significant results are shown in italics.
Figuras y tablas -
Table 5. Effect estimates (network meta‐analysis)
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Table 6. Treatment costs (tabular results without meta‐analysis)

Study name

Comparison

Mean in intervention group

Standard deviation in intervention group

Number of participants in intervention group

Mean in control group

Standard deviation in control group

Number of participants in control group

Mean difference and 95% confidence intervals (according to Review Manager formula)

Hamdy 2014

Paracentesis plus systemic vasoconstrictors versus paracentesis plus fluid replacement

10.5 USD

0.1 USD

25

856.1 USD

119.6 USD

25

‐845.60 (95% CI ‐892.48 to ‐798.72)

Singh 2006a

Paracentesis plus systemic vasoconstrictors versus paracentesis plus fluid replacement

1629.0 USD

76.7 USD

20

3368.0 USD

82.5 USD

20

‐1739.00 (95% CI ‐1788.37 to ‐1689.63)

Singh 2008

Paracentesis plus systemic vasoconstrictors versus paracentesis plus fluid replacement

29.4 USD

2.7 USD

20

105.7 USD

25.4 USD

20

‐76.30 (95% CI ‐87.49 to ‐65.11)

Mehta 1998

Paracentesis plus reinfusion versus paracentesis plus fluid replacement

295 USD

not reported

10

440 USD

Not reported

10

‐ 105; no information to calculate the 95% confidence intervals

Abbreviations:

USD = United States Dollar
CI = confidence intervals

Figuras y tablas -
Table 6. Treatment costs (tabular results without meta‐analysis)
Ir a la tabla de la revisión
Table 7. Effect estimates (Subgroup: grade 3 ascites only)

This table is too wide to be displayed in RevMan. This table can be found at: https://doi.org/10.5281/zenodo.3604780.

The table provides the network meta‐analysis effect estimates for the subgroup of grade 3 ascites only of each pairwise comparison for the different outcomes. To identify the effect estimate of a comparison, say A versus B, look at the cell that occupies the row corresponding to intervention A and the column corresponding to intervention B for the direct effect estimate. If that cell is empty (indicated by a '‐'), look at the row corresponding to intervention B and the column corresponding to intervention A. Take the inverse of this number (i.e. 1/number) to arrive at the treatment effect of A versus B.

Statistically significant results are shown in italics.

Abbreviations:

HR = hazard ratio; OR = odds ratio
Figuras y tablas -
Table 7. Effect estimates (Subgroup: grade 3 ascites only)
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Table 8. Effect estimates (Subgroup: refractory or recurrent ascites only)

This table is too wide to be displayed in RevMan. This table can be found at: https://doi.org/10.5281/zenodo.3604784.

The table provides the network meta‐analysis effect estimates for the subgroup of refractory or recurrent ascites only of each pairwise comparison for the different outcomes. To identify the effect estimate of a comparison, say A versus B, look at the cell that occupies the row corresponding to intervention A and the column corresponding to intervention B for the direct effect estimate. If that cell is empty (indicated by a '‐'), look at the row corresponding to intervention B and the column corresponding to intervention A. Take the inverse of this number (i.e. 1/number) to arrive at the treatment effect of A versus B.

Statistically significant results are shown in italics.

Abbreviations:

HR = hazard ratio
OR = odds ratio

Figuras y tablas -
Table 8. Effect estimates (Subgroup: refractory or recurrent ascites only)
Ir a la tabla de la revisión