Ligadura con banda versus intervención simulada o ninguna intervención para la profilaxis primaria de la hemorragia por várices esofágicas en niños y adolescentes con enfermedad hepática crónica o trombosis de la vena porta
Resumen
Antecedentes
La hipertensión portal suele acompañar a la enfermedad hepática avanzada y a menudo da lugar a complicaciones potencialmente mortales, incluida la hemorragia de las várices esofágicas y gastrointestinales. Las hemorragias varicosas suelen producirse en niños y adolescentes con enfermedades hepáticas crónicas o trombosis de la vena porta. Por lo tanto, la prevención es importante. Los ensayos clínicos aleatorizados han mostrado que los betabloqueantes no selectivos y la ligadura endoscópica de las várices disminuyen la incidencia de la hemorragia por várices en los adultos. En niños y adolescentes, se han propuesto la ligadura con banda, los betabloqueantes y la escleroterapia como alternativas de profilaxis primaria para la hemorragia por várices esofágicas. Sin embargo, se desconoce si estas intervenciones son beneficiosas o perjudiciales cuando se utilizan para la profilaxis primaria en niños y adolescentes.
Objetivos
Evaluar los efectos beneficiosos y perjudiciales de la ligadura con banda en comparación con una intervención simulada o ninguna intervención para la profilaxis primaria de la hemorragia por várices esofágicas en niños y adolescentes con enfermedad hepática crónica o trombosis de la vena porta.
Métodos de búsqueda
Se realizaron búsquedas en el Registro de ensayos controlados del Grupo Cochrane Hepatobiliar (Cochrane Hepato‐Biliary Group), CENTRAL, PubMed, Embase y otras dos bases de datos (abril de 2020). Se examinaron las listas de referencias de las publicaciones identificadas y también se realizaron búsquedas manuales en los libros de resúmenes de los dos principales congresos de gastroenterología y hepatología pediátrica desde enero de 2008 hasta diciembre de 2019. Se realizaron búsquedas de ensayos en curso en clinicaltrials.gov, la Food and Drug Administration (FDA) de Estados Unidos, la Agencia Europea de Medicamentos (EMA) y en la Organización Mundial de la Salud (OMS). No hubo restricciones de idioma ni de tipo de documento en la búsqueda.
Criterios de selección
El objetivo fue incluir ensayos clínicos aleatorizados, independientemente del cegamiento, el idioma o el estado de publicación, para evaluar los efectos beneficiosos y perjudiciales de la ligadura con banda versus una intervención simulada o ninguna intervención para la profilaxis primaria de la hemorragia por várices esofágicas en niños con enfermedad hepática crónica o trombosis de la vena porta. Si la búsqueda de ensayos clínicos aleatorizados recuperaba estudios cuasialeatorizados y otros estudios observacionales, se leyeron para obtener información sobre los efectos perjudiciales.
Obtención y análisis de los datos
Se utilizó la metodología Cochrane estándar para realizar esta revisión sistemática. Se utilizó GRADE para evaluar la calidad de la evidencia de cada desenlace. Los desenlaces principales fueron la mortalidad por todas las causas, los eventos adversos graves y la morbilidad relacionada con el hígado, así como la calidad de vida. Los desenlaces secundarios incluyeron la hemorragia por várices esofágicas y los eventos adversos no considerados graves. Se utilizó el principio de intención de tratar. Los datos se analizaron mediante Review Manager 5.
Resultados principales
Un resumen de conferencia, que describía un ensayo clínico aleatorizado multicéntrico de viabilidad, cumplió los criterios de inclusión de esta revisión. Se consideró que el ensayo tenía un alto riesgo de sesgo. Este ensayo se realizó en tres centros hospitalarios del Reino Unido. El objetivo del ensayo fue determinar la viabilidad y la seguridad de otros ensayos clínicos aleatorizados más grandes sobre la ligadura profiláctica con banda versus ningún tratamiento activo en niños con hipertensión portal y várices esofágicas grandes. Doce niños recibieron una ligadura con banda profiláctica y diez niños no recibieron tratamiento activo. No se proporcionó información sobre la edad ni sobre el diagnóstico de los niños incluidos. Todos los niños tuvieron un seguimiento de al menos seis meses. La mortalidad fue del 8% (1/12) en el grupo de ligadura con banda versus el 0% (0/10) en el grupo de ninguna intervención activa (razón de riesgos [RR] 2,54; intervalo de confianza [IC] del 95%: 0,11 a 56,25; evidencia de certeza muy baja). El resumen no informó cuándo se produjo la muerte, pero se supone que ocurrió entre los seis meses de seguimiento y el año. Ningún niño (0%) del grupo de ligadura con banda presentó eventos adversos (RR 0,28; IC del 95%: 0,01 a 6,25; evidencia de certeza muy baja), pero un niño de diez (10%) del grupo de ninguna intervención activa desarrolló púrpura trombocitopénica idiopática. Un niño de 12 (8%) del grupo de ligadura con banda fue sometido a trasplante de hígado versus ninguno del grupo de ninguna intervención activa (0%) (RR 2,54; IC del 95%: 0,11 a 56,25; evidencia de certeza muy baja). El ensayo no informó otros eventos adversos graves ni de morbilidad relacionada con el hígado. No se informó sobre la calidad de vida. La hemorragia por várices esofágicas se produjo en el 8% (1/12) de los niños del grupo de ligadura con banda versus el 30% (3/10) de los niños del grupo de ninguna intervención activa (RR 0,28; IC del 95%: 0,03 a 2,27; evidencia de certeza muy baja). No se informaron eventos adversos considerados no graves. Dos niños se perdieron en el seguimiento al año. Diez niños en total completaron el ensayo en el seguimiento a los dos años. No hubo información sobre la financiación.
Se encontraron dos estudios observacionales sobre la ligadura endoscópica de várices al buscar ensayos aleatorizados. Uno de ellos no encontró efectos perjudiciales y el otro informó una sepsis por Enterobactercloacae en un niño y una estenosis leve y transitoria del esfínter esofágico superior en otro. No se evaluó el riesgo de sesgo de estos estudios.
No se encontraron ensayos clínicos aleatorizados en curso de interés para esta revisión.
Conclusiones de los autores
La evidencia, obtenida de un solo ensayo clínico aleatorizado de viabilidad con alto riesgo de sesgo, es muy escasa. No está claro si la ligadura profiláctica con banda versus una intervención simulada o ninguna intervención (activa) puede afectar a la mortalidad, los eventos adversos graves y la morbilidad relacionada con el hígado, o la hemorragia por várices esofágicas en niños y adolescentes con hipertensión portal y várices esofágicas grandes. No hubo datos sobre la calidad de vida. No se informaron eventos adversos considerados no graves. Los resultados presentados en el ensayo se deben interpretar con precaución. Además, los datos, muy limitados, sólo cubren una parte de la pregunta de investigación, es decir, los niños con hipertensión portal y várices esofágicas grandes. Se carece de datos sobre los niños con trombosis de la vena porta.
Se necesitan ensayos clínicos aleatorizados más grandes que evalúen los efectos beneficiosos y perjudiciales de la ligadura con banda en comparación con el tratamiento simulado para la profilaxis primaria de la hemorragia por várices esofágicas en niños y adolescentes con enfermedad hepática crónica o trombosis de la vena porta. Los ensayos deben incluir desenlaces clínicos importantes como la muerte, la calidad de vida, el fracaso en el control de la hemorragia y los eventos adversos.
PICO
Resumen en términos sencillos
En los niños con enfermedades hepáticas, que tienen venas dilatadas en el esófago (tubo de alimentación), ¿la colocación de un anillo elástico alrededor de la vena evita que ésta sangre?
Hemorragia en el esófago
Un coágulo de sangre en las venas que drenan la sangre del tubo digestivo hacia el hígado (conocido como trombosis de la vena porta) provoca un aumento de la presión en estas venas. El aumento de la presión sanguínea en las venas que suministran sangre al hígado también es frecuente en las enfermedades hepáticas graves. El aumento de la presión puede hacer que las venas del esófago (el tubo que va de la garganta al estómago) se hinchen y dilaten. La hemorragia de las venas dilatadas en el esófago es una afección potencialmente mortal.
¿Cómo se tratan las venas dilatadas en el esófago?
En los adultos, los estudios han mostrado que hay dos tratamientos que funcionan bien para tratar las hemorragias de las venas dilatadas:
‐ tomar medicamentos llamados betabloqueantes; y
‐ colocar un anillo elástico alrededor de la vena para cortar el flujo de sangre a través de ella.
Estos dos tratamientos se han convertido en las principales formas de prevenir las hemorragias por venas dilatadas en el esófago en los adultos. Sin embargo, no sabemos hasta qué punto estos tratamientos funcionan en los niños y los jóvenes, o si causan efectos no deseados o perjudiciales.
¿Por qué se ha elaborado esta revisión Cochrane?
Se querían evaluar los efectos beneficiosos y perjudiciales de la colocación de un anillo elástico alrededor de una vena dilatada para evitar la hemorragia, en niños con enfermedad hepática de larga duración o trombosis de la vena porta.
Qué se hizo
Se buscaron los estudios que analizaran los efectos de la colocación de un anillo elástico alrededor de una vena dilatada en el esófago para evitar su hemorragia, en comparación con un tratamiento simulado (el mismo procedimiento, pero sin colocación de una banda) o ningún tratamiento, en niños con enfermedad hepática de larga duración o trombosis de la vena porta.
Se buscaron estudios clínicos aleatorizados, en los que las personas que participan se colocan al azar en diferentes grupos de intervención. Este tipo de estudio, si se realiza correctamente, suele aportar la evidencia más fiable sobre los efectos de un tratamiento.
Se deseaba determinar lo siguiente:
‐ cuántos niños murieron;
‐ cuántos niños presentaron efectos no deseados graves (efectos considerados potencialmente mortales o que necesitaron tratamiento hospitalario) o enfermedades relacionadas con el hígado;
‐ el bienestar de los niños (calidad de vida);
‐ cuántos niños presentaron hemorragia esofágica; y
‐ cuántos niños presentaron efectos no deseados que no se consideraron graves.
¿Qué tan actual es la evidencia?
La evidencia de esta revisión incluye estudios de investigación publicados hasta el 27 de abril de 2020.
Qué se encontró
Sólo se encontró una publicación de un estudio que se realizó en tres hospitales del Reino Unido. Se trataba de un estudio de viabilidad: que observaba si era posible realizar estudios aleatorizados más grandes y concluyentes. Se publicó un resumen de los datos del estudio y se presentó en una conferencia. La publicación del estudio no fue lo suficientemente buena para evaluar la calidad del estudio. No se proporcionó información sobre la financiación.
No se encontraron otros estudios que se pudieran incluir en esta revisión y no hay estudios aleatorizados en curso.
¿Cuáles son los principales resultados?
El estudio distribuyó al azar a 22 niños con hipertensión portal y venas dilatadas en dos grupos:
‐ a un grupo se le colocó un anillo elástico alrededor de la vena dilatada (12 niños); y
‐ un grupo no recibió tratamiento activo (diez niños).
No se proporcionó información sobre el diagnóstico ni la edad de los niños. Los niños recibieron seguimiento durante al menos seis meses. Dos niños se perdieron en el seguimiento al año. Sólo diez niños en total completaron el estudio del ensayo a los dos años de seguimiento.
En el grupo al que se le colocó un anillo elástico:
‐ un niño murió;
‐ ningún niño presentó otros efectos no deseados graves;
‐ un niño necesitó un trasplante de hígado; y
‐ un niño presentó una hemorragia esofágica.
En el grupo que no recibió tratamiento activo:
‐ ningún niño murió;
‐ un niño tuvo un efecto no deseado grave: un trastorno inmunológico en el que la sangre no coagula correctamente (púrpura trombocitopénica idiopática);
‐ ningún niño necesitó un trasplante de hígado; y
‐ tres niños presentaron hemorragia esofágica.
No se notificaron efectos no deseados menos graves en ninguno de los dos grupos. El estudio no aportó información sobre el bienestar de los niños (calidad de vida).
Conclusiones
El informe insuficiente y deficiente de los resultados de un pequeño estudio aleatorizado, y la falta de otros estudios aleatorizados, hacen que no sea posible establecer conclusiones fiables. No se sabe qué eficacia tienen los anillos elásticos para prevenir las hemorragias por venas dilatadas en el esófago en niños y jóvenes, ni tampoco los efectos no deseados que puedan causar.
Hasta que no se realicen estudios aleatorizados de buena calidad y se mida el número de muertes, la calidad de vida, el fracaso en el control de las hemorragias y los efectos no deseados, no se sabrá si los anillos elásticos son un buen tratamiento para prevenir las hemorragias en niños y jóvenes con enfermedades hepáticas de larga duración o trombosis de la vena porta.
Authors' conclusions
Summary of findings
| Band ligation versus sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis | ||||||
| Patient or population: children with portal hypertension and large oesophageal varices, without previous gastrointestinal bleeding or beta‐blocker treatment | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with sham or no intervention | Risk with band ligation | |||||
| All‐cause mortality at minimum 6 months* | 0 per 1,000 | 0 per 1,000 | RR 2.54 | 22 | ⊝⊝⊝⊝ | All‐cause mortality was 8% (1/12) in the band ligation group and 0% (0/10) in the no active intervention group |
| Serious adverse events Idiopathic thrombocytopaenic purpura Follow‐up: at minimum 6 months* and Liver‐related morbidity: ‐ liver transplantation | 100 per 1,000 | 28 per 1,000 | RR 0.28 (0.01 to 6.25) | 22 | ⊕⊝⊝⊝ Very low 2 | 0 out of 12 children (0%) in the band ligation group developed idiopathic thrombocytopaenic purpura versus 1 out of 10 (10%) in the no active intervention group. |
| 0 per 1,000 | 0 per 1,000 | RR 2.54 | 22 | ⊕⊝⊝⊝ Very low 2 | 1/12 children (8%) randomised to band ligation underwent liver transplantation while 0/10 children (0%) in the no active intervention group underwent liver transplantation | |
| Health‐related quality of life | Outcome not assessed in the trial | |||||
| Oesophageal variceal bleeding | 300 per 1,000 | 84 per 1,000 | RR 0.28 | 22 | ⊕⊝⊝⊝ | Oesophageal variceal bleeding occurred in 8% (1/12) of the children in the band ligation group and in 30% (3/10) of the children in the no active intervention group. |
| Adverse events considered not serious Follow‐up: at minimum 6 months* | Not assessable | Not reported | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio; RCT: randomised clinical trial; OIS: optimal information size | ||||||
| GRADE Working Group grades of evidence | ||||||
| * Although the trial abstract reported the maximum follow‐up to be two years, it did not specify the time when events occurred for all participants. The trial reported: "All have completed at least six months follow‐up; after the first year the treatment protocol was relaxed to allow fewer variceal band ligation sessions; and 10 have completed the study." 10 children in total seemed to have completed the trial at two‐year follow‐up. 1 Downgraded because of: risk of bias (two levels): blinding of participants and personnel (performance bias) was at high risk of bias, and all other domains were at unclear risk of bias; imprecision (two levels): few events; and the CI of the point estimate is very wide and includes both benefit and harm. 2Downgraded because of: risk of bias (two levels): blinding of participants and personnel (performance bias) was at high risk of bias, and all other domains were at unclear risk of bias; imprecision (two levels): the OIS of 2005 participants was not met; few events; and the CI of the point estimate is very wide and includes both benefit and harm. 3Downgraded because of: risk of bias (two levels): blinding of participants and personnel (performance bias) was at high risk of bias, and all other domains were at unclear risk of bias; imprecision (two levels): the OIS of 540 participants was not met; few events; and the CI of the point estimate includes both benefit and harm. | ||||||
Background
Description of the condition
There are scarce data on the prevalence and burden of liver disease in children and adolescents. However, we know that the natural history of portal hypertension in children and adolescents is different from that in adults. In adults, the cause of portal hypertension is mostly intrahepatic, whereas the cause in children is mostly extrahepatic. The main underlying condition which results in the development of portal hypertension in children is extrahepatic portal vein thrombosis (Di Giorgio 2019), followed by cirrhotic aetiologies, such as biliary atresia (Shneider 2016; Chapin 2018). In adults with portal hypertension, hepatic venous pressure gradient (HVPG) of 10 mmHg or more has been associated with the formation of oesophageal varices, variceal bleeding or ascites, or both (Ebel 2019). The risk of oesophageal variceal bleeding is increased at HVPG of 12 mmHg or more (de Franchis 2015). However, there are limited data on HVPG gradient in children. A recent study in children with portal hypertension found that HVPG was not associated with the presence of varices or history of variceal bleeding, suggesting the possibility of intrahepatic shunting in children with advanced liver disease (Ebel 2019). The study by Ebel 2019 also suggested that "the use of HVPG measurements alone may not capture all children at risk for adverse clinical outcomes secondary to portal hypertension".
Variceal haemorrhage (bleeding) is common in children with portal hypertension due to a chronic liver disease or portal vein thrombosis (Lykavieris 2000; Miga 2001; Van Heurn 2004; Di Giorgio 2019). A study of 125 children with biliary atresia, with signs of portal hypertension or previous history of gastrointestinal bleeding, reported that 88 children (70%) developed oesophageal varices (Duche 2010). Several other studies reported incidence of variceal haemorrhage in children with biliary atresia within the range of 15% to 29% (Miga 2001; Van Heurn 2004; Shneider 2012b; Lee 2017; Van Wessel 2018). Goncalves 2000 prospectively followed 50 children with oesophageal varices that were primarily due to cirrhosis. None of the children received active treatment to prevent variceal bleeding. In this study, 42% suffered upper gastrointestinal haemorrhage within a median follow‐up period of 4.5 year (Goncalves 2000). For children with portal vein thrombosis, studies suggest that up to 50% of the children suffer a major variceal haemorrhage by the age of 16 (Lykavieris 2000). A more recent study by Di Giorgio 2019, including 187 patients with portal hypertension due to non‐cirrhotic portal vein thrombosis, found that 67 (36%) patients were diagnosed following gastrointestinal bleeding. Of the 71 patients who had endoscopy at presentation, 62 (87%) had oesophageal varices (Di Giorgio 2019).
A mortality rate of 19% was reported within 35 days of variceal bleeding episodes among North American children with liver disease of various aetiologies (Eroglu 2004). Two other studies showed that 5% and 15% of children with biliary atresia and variceal bleeding were expected to die (Stringer 1989; Van Heurn 2004, respectively). In contrast, variceal bleeding in children with portal vein thrombosis and no parenchymal liver disease seemed to carry a lower risk of death (i.e. less than 3%) (Lykavieris 2000).
Specific endoscopic variceal patterns have been shown to be predictive of the risk of gastrointestinal bleeding. Grade 1 varices are small varices that extend just above the mucosal level. Grade 2 varices project in less than one‐third of the luminal diameter and cannot be compressed with air insufflation. Grade 3 varices are large varices that occupy more than one‐third of the luminal diameter. In children with biliary atresia, grade 3 varices and grade 2 varices with oesophageal red markings and the presence of gastric varices, have been reported to be independent risk factors for bleeding (Duche 2013; Duche 2017). However, the data regarding endoscopic pattern of gastroesophageal varices predicting high risk of bleeding in children with portal vein thrombosis and other causes of portal hypertension are limited (Shneider 2016; Chapin 2018; Quintero 2019; Quintero 2020).
Description of the intervention
Band ligation is an endoscopic procedure in which an enlarged vein in the oesophagus is ligated by a rubber band. Numerous randomised clinical trials have shown the benefits of non‐selective beta‐blockers and endoscopic variceal band ligation as treatment modalities against acute variceal haemorrhage in adults. These interventions are also the established standard of primary prevention in adults (Garcia‐Tsao 2007; Garcia‐Tsao 2008; Gluud 2012; Garcia‐Tsao 2017). No evidence‐based recommendations for the prophylactic management of variceal haemorrhage in children and adolescents at risk exist because of the lack of appropriate, good quality, randomised clinical trials (Shneider 2016).
There are several differences in the pathophysiology of portal hypertension in adults versus in children and adolescents, so extrapolation of results from the former to the latter must be done cautiously. The principal aetiologies of liver disease and portal hypertension are different in these populations. In children, the main causes of portal hypertension are biliary atresia and portal vein thrombosis, while in adults they are hepatitis C and alcohol‐related cirrhosis. Although band ligation is frequently used in children, there is a limitation, as the band ligation device currently available is too large to be introduced into the oesophagi of children weighing less than 10 kg.
How the intervention might work
Endoscopic variceal ligation and beta‐blockers have been shown to be the best treatment modalities in adults (Garcia‐Tsao 2007; Garcia‐Tsao 2008; Gluud 2012; Garcia‐Tsao 2017). Band ligation leads to mechanical obliteration of the varices, reducing the intra‐varix blood flow. A 2001 meta‐analysis showed that endoscopic variceal ligation for primary prophylaxis of oesophageal varices in adults with cirrhosis reduced the incidence of variceal haemorrhage and mortality by 64% compared with no therapy (Imperiale 2001). Moreover, band ligation seems to be superior compared with beta‐blockers in reducing variceal bleeding (Gluud 2012). Considering this information, it seems reasonable to consider this intervention as a prophylactic option in children and adolescents with oesophageal varices (Bozic 2015; Pimenta 2016).
Why it is important to do this review
Variceal haemorrhage commonly occurs in children and adolescents with oesophageal varices secondary to chronic liver disease or portal vein thrombosis, and, as it has been associated with mortality (Mileti 2011; Chapin 2018), prevention is important. Identification of how to prevent it is one of the most important areas that needs to be addressed in children with portal hypertension (Gana 2010; Gana 2011b; Ling 2011; Shneider 2012a). There are no systematic reviews or meta‐analyses of randomised clinical trials on this topic at present.
Surveys of paediatric gastroenterologists indicate that they adopt different approaches to primary prophylaxis of variceal bleeding in children with portal hypertension (Shneider 2004; Gana 2011a; Verdaguer 2016; Jeanniard‐Malet 2017). In a survey of 30 paediatric gastroenterologists in the USA, 63% of the respondents performed surveillance of oesophageal varices and 84% offered primary prophylaxis of variceal bleeding in children (Shneider 2004). In a survey of 47 paediatric gastroenterologists in Canada, 70% reported that they would consider screening for oesophageal varices in children with liver disease, and evidence of cirrhosis or portal hypertension (such as splenomegaly, thrombocytopenia, or portosystemic collaterals on sonography). However, only 58% of the respondents who would screen for varices would provide primary prophylaxis (Gana 2011a). The results of these surveys suggest that many paediatric specialists apply the guidelines for the management of adults with portal hypertension to children. However, the primary prophylaxis provided by physicians varies considerably, probably due to the lack of evidence from good‐quality randomised clinical trials.
Different treatments have been proposed for the primary prophylaxis of oesophageal variceal bleeding in children. This systematic review is one of six reviews that examines the utility of these treatment modalities, i.e. band ligation versus sham or no intervention, for primary prophylaxis of oesophageal varices bleeding in children with chronic liver disease or portal vein thrombosis (Gana 2015). The remaining reviews examine beta‐blockers versus placebo (Cifuentes 2021), band ligation versus sclerotherapy (Gana 2020), band ligation versus beta‐blockers (Gana 2019), sclerotherapy versus sham or no intervention (Gattini 2020a), and sclerotherapy versus beta‐blockers (Gattini 2020b) for the same target population and disease.
Objectives
To assess the benefits and harms of band ligation compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis.
Methods
Criteria for considering studies for this review
Types of studies
Randomised clinical trials, regardless of publication status, language, or blinding. The trials should have compared band ligation versus sham or no intervention, performed as primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis.
If quasi‐randomised and observational studies were retrieved with the search results for randomised clinical trials, we planned to extract data on harm and present a narrative summary of the reported harm. This is because adverse events are rarely reported in randomised clinical trials (Storebø 2018). Moreover, observational studies may provide information on rare or late‐occurring adverse events (Storebø 2018).
Types of participants
Children (up to 18 years old) with chronic liver disease or portal vein thrombosis, irrespective of the aetiology, severity of disease, and duration of illness, in whom the presence of oesophageal varices is confirmed by oesophagogastroduodenoscopy. The review focuses on therapy questions related to children and adolescents who have not yet suffered gastrointestinal bleeding from oesophageal varices (primary prophylaxis).
Children with a previous surgical portal‐systemic shunt procedure or insertion of a transjugular intrahepatic portal‐systemic shunt (TIPS), previous sclerotherapy, or ligation of oesophageal varices, or previous history of upper gastrointestinal bleeding, comprise a distinct group in whom the diagnosis or natural history of oesophageal varices has been modified. These types of participants were not the focus of our review, and we excluded them unless the study report allowed us to extract only the data of relevance to our study population.
We also planned to exclude children with previous use of beta‐blockers.
Types of interventions
Experimental
-
endoscopic band ligation of oesophageal varices
Control
-
sham or no intervention
Co‐interventions were allowed if administered equally to the intervention groups in a trial.
Types of outcome measures
Primary outcomes
-
All‐cause mortality
-
Serious adverse events and liver‐related morbidity (i.e. proportion of participants who developed ascites, hepatorenal syndrome, hepatocellular carcinoma or hepatic encephalopathy). According to the International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (ICH‐GCP 1997), a serious adverse event is any untoward medical occurrence that: results in death; is life‐threatening; requires inpatient hospitalisation or prolongation of existing hospitalisation; results in persistent or significant disability or incapacity; or is a congenital anomaly or birth defect. All other adverse events were considered non‐serious adverse events.
-
Quality of life, determined exclusively by means of validated scales, classifications and measurement systems like the Paediatric Quality of Life Inventory (PedsQL), Child Health Questionnaire (CHQ), and DISABKIDS Questionnaire.
Secondary outcomes
-
Oesophageal variceal bleeding
-
Adverse events considered not serious (any adverse events that do not meet the above criteria for serious adverse events)
We planned to collect follow‐up data for the listed outcomes during the trial period, and up to five years follow‐up (the primary time point for analysis for conclusions).
Search methods for identification of studies
Electronic searches
We searched the Cochrane Hepato‐Biliary Group Controlled Trials Register (maintained and searched internally by the Cochrane Hepato‐Biliary Group Information Specialist via the Cochrane Register of Studies Web; April 2020); Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 4) in The Cochrane Library (searched April 2020); PubMed (1809 to April 2020); Embase (Elsevier; 1974 to April 2020); LILACS (Latin American and Caribbean Health Science Information database; 1982 to April 2020); and Science Citation Index Expanded (Web of Science; 1900 to April 2020) (Royle 2003). We scrutinised the reference lists of the retrieved publications. We also searched the trial registries ClinicalTrial.gov (clinicaltrials.gov/), European Medicines Agency (EMA) (www.ema.europa.eu/ema/), World Health Organization (WHO) International Clinical Trial Registry Platform (ICTRP) (www.who.int/ictrp), and the Food and Drug Administration (FDA) (www.fda.gov) for ongoing trials. Due to heavy traffic generated by the COVID‐19 outbreak, the ICTRP Search Portal temporarily was not accessible from outside WHO. However, trials from both ClinicalTrials.gov and the WHO trials register are included in CENTRAL. We did not limit our search by language or document type. Search strategies with the time spans of the searches are listed in Appendix 1.
Searching other resources
We identified additional references by handsearching the references of articles from the computerised databases and relevant review articles. Furthermore, we also performed a handsearch of the abstract books for the main paediatric gastroenterology and hepatology conferences (North American Society For Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and European Society For Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)) from January 2008 to December 2019.
Data collection and analysis
We followed the guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The analyses were performed using Review Manager 5 (Review Manager 2014).
Selection of studies
We retrieved publications if they were potentially eligible for inclusion based on an abstract review, or if they were relevant review articles for a handsearch of references. Lorena Cifuentes (LC) and Daniela Gattini (DG) independently screened the publications for eligibility. We assessed for eligibility each publication in order to determine if participants met the inclusion criteria detailed above. We planned to include abstracts only if sufficient data were provided for analysis. We considered for inclusion trials published in full, regardless of whether they reported the outcomes of interest or not. We resolved any disagreements by reaching consensus between LC, DG, and Juan Cristóbal Gana (JCG).
Data extraction and management
Two authors (LC and DG) independently completed the data extraction form for the included study and retrieved the following data.
-
General information: title, journal, year, publication status, and trial design.
-
Sponsor of the trial.
-
Sample size: number of participants meeting the criteria and total number screened.
-
Baseline characteristics: baseline diagnosis, age, sex, race or ethnicity, disease severity, and concurrent medications used.
-
Severity of liver disease of the studied population measured using the Child‐Pugh score (Pugh 1973), the paediatric end‐stage liver disease (PELD) scores for children younger than 12 years (McDiarmid 2002), and the model for end‐stage liver disease (MELD) scores for children aged 12 and older (Kamath 2001).
-
All‐cause mortality, non‐variceal bleeding of the upper gastrointestinal tract, oesophageal variceal bleeding and quality of life determined exclusively by validated scales.
-
Adverse events: serious and non‐serious.
JCG arbitrated where there were disagreements about data extraction.
Assessment of risk of bias in included studies
Two review authors (LC and JCG) independently assessed the risk of bias in the included trial according to the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and methodological studies (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Savović 2012a; Savović 2012b; Savović 2018). We used the following definitions in the assessment of risk of bias.
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.
Allocation concealment
-
Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomisation unit. The allocation sequence was unknown to the investigators (e.g. if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).
-
Unclear risk of bias: the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during, enrolment.
-
High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants.
Blinding of participants and personnel
-
Low risk of bias: blinding of participants and personnel performed adequately using a placebo. We defined lack of blinding as not likely to affect the evaluation of mortality (Savović 2012a; Savović 2012b).
-
Unclear risk of bias: insufficient information to assess blinding.
-
High risk of bias: no blinding or incomplete blinding.
Blinding of outcome assessors
-
Low risk of bias: blinding of outcome assessors performed adequately using a placebo. We defined lack of blinding as not likely to affect the evaluation of mortality (Savović 2012a; Savović 2012b).
-
Unclear risk of bias: insufficient information to assess blinding.
-
High risk of bias: no blinding or incomplete blinding.
Incomplete outcome data
-
Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, were employed 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: the trial reported the following pre‐defined primary outcomes: 'all‐cause mortality' and 'serious adverse events and liver‐related morbidity'. If the original trial protocol was available, the outcomes should be those called for in that protocol. If the trial protocol was obtained from a trial registry (e.g. www.clinicaltrials.gov), the outcomes sought were 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 commenced, those outcomes were not considered to be reliable.
-
Unclear risk: not all pre‐defined outcomes were reported fully, or it was unclear whether data on these outcomes were recorded or not.
-
High risk: one or more pre‐defined outcomes were not reported.
Other bias
-
Low risk of bias: the trial appeared to be free of other bias domains including vested interests that could put it at risk of bias.
-
Unclear risk of bias: the trial may or may not have been free of other domains 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
Overall bias risk assessment
-
Low risk of bias: all domains in a trial were at low risk of bias using the definitions described above.
-
High risk of bias: one or more of the bias domains in a trial were at unclear or high risk of bias.
Measures of treatment effect
Dichotomous outcomes
For dichotomous outcomes, we calculated the risk ratio (RR) with 95% confidence intervals (CIs). We also planned to use odds ratios if the incidence of an outcome was rare (below 5%).
Continuous outcomes
For continuous outcomes, we planned to calculate the mean difference (MD) with 95% CI if all trials reported quality of life using the same scale, and standardised mean difference (SMD) with 95% CI if the trials used different scales to report quality of life.
Unit of analysis issues
The unit of analysis was the participant undergoing treatment (i.e. primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis) according to the intervention group to which the participant was randomly assigned. In case of trials with multiple intervention groups, we planned to collect data for all trial intervention groups that met our inclusion criteria. We planned to divide the control intervention group into two to avoid double‐counting in case this was a common comparator. In the case of cross‐over trials, we planned to use the outcome data after the period of first intervention because the assigned treatments could have residual effects (Higgins 2011). Due to the clinical situation, we did not expect to find cluster‐randomised trials.
Dealing with missing data
We planned to perform an intention‐to‐treat analysis whenever possible; otherwise, we planned to analyse only the data available to us and to contact the original investigators to request any missing data. We planned to address the potential impact of missing data on the findings using intention‐to‐treat analyses.
Regarding the dichotomous primary outcomes, whenever possible, we planned to include participants with incomplete or missing data in sensitivity analyses, by imputing data according to the following scenarios.
-
Extreme‐case analysis favouring the experimental intervention group ('best‐worse' case scenario): none of the dropouts or participants lost from the experimental group, but all of the dropouts and participants lost from the control intervention group experienced the outcome; including all randomised participants in the denominator.
-
Extreme‐case analysis favouring the control intervention group ('worst‐best' case scenario): all dropouts or participants lost from the experimental group, but none from the control group experienced the outcome; including all randomised participants in the denominator.
For the continuous primary outcome, quality of life, we planned to impute the standard deviation from P values, according to guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011; Higgins 2020). If the data were likely to be normally distributed, we planned to use the median for meta‐analysis when the mean was not available; otherwise, we planned to 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 CIs, 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 MDs and may bias the effect estimate to no effect for calculation of SMDs (Higgins 2011; Higgins 2020).
Assessment of heterogeneity
We planned to identify heterogeneity by visual inspection of the forest plots, by using a standard Chi2 test and a significance level of α = 0.1, in view of the low power of such tests. We planned to use the Chi2 test for heterogeneity to detect between‐trial heterogeneity. In addition, we planned to specifically examine the degree of heterogeneity observed in the results with I2 statistic according to the following classification: from 0% to 40%, heterogeneity may not be important; from 30% to 60%, heterogeneity may be moderate; from 50% to 90%, heterogeneity may be substantial; and from 75% to 100%, heterogeneity may be considerable (Higgins 2003). If heterogeneity was found, we planned to determine the potential reasons for it by examining the individual trial and subgroup characteristics.
Assessment of reporting biases
We planned to assess reporting biases with funnel plots of the relative risk estimates from the individual trials (plotted on a logarithmic scale) against trial size or precision (variance) or the estimators in case there were at least 10 trials.
Data synthesis
Meta‐analyses
We planned to conduct this systematic review according to the recommendations set out in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We planned to use the statistical software Review Manager 5 provided by Cochrane to analyse data and produce summary estimates of the treatment effect (Review Manager 2014). We planned to present results with a random‐effects meta‐analysis because we expected that the included trials would be heterogeneous. We planned to present results of continuous outcomes as MD or SMD, both with 95% CI.
We planned to perform a meta‐regression to examine heterogeneity.
Subgroup analysis and investigation of heterogeneity
We planned to perform the following subgroup analyses because we expected that we would observe heterogeneity.
-
Trials at low risk of bias compared to trials at high risk of bias because trials at high risk of bias may overestimate or underestimate a treatment effect (Higgins 2011).
-
Trials at risk of for‐profit bias compared to trials at no risk of for‐profit bias (post‐hoc) (Lundh 2017).
-
Primary prophylaxis of small varices compared to primary prophylaxis of only medium or large varices because of the different risk of bleeding according to the variceal size (Garcia‐Tsao 2017).
-
Children with chronic liver disease compared to children with extrahepatic portal vein thrombosis because of the differences in the physiopathology of the cause of the portal hypertension in patients with liver disease versus alteration in the portal inflow (Chapin 2018).
-
Severity of liver disease (Child‐Pugh A, B, or C, and PELD or MELD) because of the different risk of bleeding according to the impaired liver function (Garcia‐Tsao 2017).
-
Children with cholestatic liver disease compared to children with non‐cholestatic liver disease because of the different risk of bleeding according to different etiologies (Chapin 2018).
Sensitivity analysis
In addition to the sensitivity analyses specified under 'Dealing with missing data', in order to assess the robustness of the eligibility criteria, our intention was to undertake further sensitivity analyses that might be able to explain our findings as well as any observed heterogeneity.
Trial Sequential Analysis
We planned to perform Trial Sequential Analysis (TSA 2011; Thorlund 2017) because cumulative meta‐analyses are at risk of producing random errors due to sparse data and repetitive testing of the accumulating data (Wetterslev 2008). To minimise random errors, we planned to calculate the required information size (i.e. the number of children needed in a meta‐analysis to detect or reject a certain intervention effect) (Wetterslev 2008).
The required information size calculation should also account for the heterogeneity or diversity present in the meta‐analysis (Wetterslev 2008; Wetterslev 2009; Wetterslev 2017). In our meta‐analyses, we planned to base the diversity‐adjusted required information size (DARIS) on: the event proportion in the control group; assumption of a plausible relative risk reduction of 20% or the relative risk reduction observed in the included trials with low risk of bias; a risk of type I error of 2.5% because of three primary outcomes and 3.3% because of two secondary outcomes; a risk of type II error of 20%; and the observed diversity of the meta‐analysis (Wetterslev 2009; Jakobsen 2014; Wetterslev 2017).
The underlying assumption of Trial Sequential Analysis is that testing for significance may be performed each time a new trial is added to the meta‐analysis. We planned to add the trials according to the year of publication, and, if more than one trial was published in a year, we planned to add trials alphabetically by last name of the first author. Based on the DARIS, we planned to construct trial sequential monitoring boundaries (Wetterslev 2008; Thorlund 2017; Wetterslev 2017). These boundaries determine the statistical inference one may draw regarding the cumulative meta‐analysis that has not reached the required information size. If the trial sequential monitoring boundary for benefit or harm is crossed before the required information size is reached, firm evidence may be established and further trials may be superfluous. However, if the boundary is not crossed, it is probably necessary to continue conducting trials in order to detect or reject a certain intervention effect. This can be determined by assessing if the cumulative Z‐curve crosses the trial sequential monitoring boundaries for futility.
We planned to downgrade our assessment for imprecision in Trial Sequential Analysis by two levels if the accrued number of participants was below 50% of the DARIS, and one level if the number was between 50% and 100% of DARIS. We planned to not downgrade our assessment of imprecision if the cumulative Z‐curve reached futility or DARIS.
Summary of findings and assessment of the certainty of the evidence
We created a 'Summary of findings' table, using GRADEpro (GRADEpro GDT), to provide information about the certainty of the evidence, the magnitude of effects of the interventions, and to summarise results on outcomes of all‐cause mortality, serious adverse events and liver‐related morbidity, quality of life, oesophageal bleeding, and non‐serious adverse events.
The GRADE approach appraises the certainty of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. The certainty of a body of evidence considers: within‐study risk of bias; indirectness of the evidence (population, intervention, control, outcomes); unexplained inconsistency (heterogeneity) of results (including problems with subgroup analyses); imprecision of results; and risk of publication bias.
We classify the levels of evidence as 'high', 'moderate', 'low', or 'very low'. These grades are defined as follows:
-
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.
Results
Description of studies
Results of the search
We identified 870 records in the initial electronic search for interventions for primary prophylaxis of oesophageal variceal bleeding in children or adolescents. We identified four additional records through handsearching the ESPGHAN and NASPGHAN conference abstract books from 2008 through 2019. After excluding duplicates, we found a total of 642 records. For this systematic review, in which band ligation is compared with sham or no intervention, we identified 98 records for abstract review. We excluded 89 of them because they did not meet the criteria for inclusion in this review (Figure 1). We assessed a total of nine full‐text publications for eligibility and for reports on harm. We excluded eight of these publications because they included adults, assessed secondary prophylaxis, or involved a different intervention (Figure 1). However, two of the eight publications reported on harm. The remaining one publication, a conference abstract, met our inclusion criteria (McKiernan 2011).
Study flow diagram. Date of search 27 April 2020.
We did not find any ongoing clinical trials assessing band ligation versus sham or no intervention for primary prophylaxis of variceal bleeding in children and adolescents.
Included studies
The conference abstract described a multi‐centre feasibility randomised clinical trial in children (McKiernan 2011). The trial was not subsequently published as a full text. The trial involved three hospital centres in the United Kingdom (UK). Sixty‐five children with portal hypertension but without previous history of gastrointestinal bleeding or beta‐blocker treatment were recruited prior to routine endoscopy. Of these, 22 children had large oesophageal varices and were randomised to receive either prophylactic band ligation (12 children) versus no active intervention (10 children). There was no information about how any of the participants were diagnosed. All children were followed for at least six months. Two children were lost to follow‐up by one‐year. Ten children in total completed the trial at two‐year follow‐up. The abstract contained no information on trial funding.
We did not find any other trial fulfilling the inclusion criteria of our review.
Excluded studies
The eight excluded studies are listed in Characteristics of excluded studies with the reasons for exclusion.
Risk of bias in included studies
The only included trial was at an overall high risk of bias: all bias domains were either at high risk of bias or unclear risk of bias (Figure 2; 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 summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Unclear risk of bias: the method of sequence generation and allocation concealment were not specified.
Blinding
High risk of bias: it is very likely that blinding of the children and the clinicians treating them was not possible as the control group received no active intervention, making this domain at high risk of bias.
Incomplete outcome 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.
Selective reporting
Unclear risk: not all pre‐defined outcomes were reported fully, or it was unclear whether data on these outcomes were recorded or not.
Other potential sources of bias
Unclear risk of bias: the trial may or may not have been free of other domains that could put it at risk of bias.
Effects of interventions
We calculated point estimates with relative risks, using RevMan analysis. We entered data based on the intention‐to‐treat principle. We did not use odds ratios as the events were higher than 5%.
Primary outcomes
All‐cause mortality
All‐cause mortality was 8% (1/12) in the band ligation group versus 0% (0/10) in the no active intervention group (RR 2.54, 95% CI 0.11 to 56.25; very low‐certainty of evidence; Analysis 1.1).
Serious adverse events and liver‐related morbidity
None of the 12 children (0%) in the band ligation group developed serious adverse events, while one child out of 10 (10%) in the no active intervention group developed a serious adverse event (RR 0.28, 95% CI 0.01 to 6.25; very low‐certainty of evidence; Analysis 1.2; summary of findings Table 1). That child developed idiopathic thrombocytopaenic purpura.
One child out of 12 (8%) in the band ligation group underwent liver transplantation, versus none in the no active intervention group (0%) (RR 2.54, 95% CI 0.11 to 56.25; very low‐certainty of evidence; Analysis 1.2; summary of findings Table 1).
No other serious adverse events were reported in either group.
Quality of life
The trial reported no data on quality of life.
Secondary outcomes
Oesophageal variceal bleeding
Oesophageal variceal bleeding occurred in 8% (1/12) of the children in the band ligation group versus 30% (3/10) of the children in the no active intervention group (RR 0.28, 95% CI 0.03 to 2.27; very low‐certainty of evidence; Analysis 1.3; summary of findings Table 1).
Adverse events considered not serious
Adverse events considered non‐serious were not reported.
Subgroup analysis
Due to the inclusion of one trial only, we could not perform any of the subgroup analyses.
Sensitivity analysis
We decided not to perform the two scenario analyses described in Dealing with missing data because there is only one included trial assessed at overall high risk of bias, and the certainty of the evidence is very low. We cannot be sure whether the two children who were lost to follow‐up continued to contribute outcome data.
We did not perform Trial Sequential Analysis because only one trial was included.
Harms observed in observational studies, retrieved with the searches for randomised trials
Two of the eight excluded studies disclosed information on harm (Celinska‐Cedro 2003; Galand 2018; Table 1).
| Study ID | Short summary | Report on harms |
|---|---|---|
| The study assessed primary prophylaxis with endoscopic variceal ligation in 37 children with portal hypertension (22 with liver cirrhosis and 15 with portal vein thrombosis). | ‐ No variceal bleeding occurred during the study period. ‐ No serious adverse events of variceal ligation were reported. The average follow‐up time was 16 months. | |
| The study assessed primary prophylaxis of digestive haemorrhage by oesophageal variceal ligation in comparison to secondary prophylaxis. 30 children were included in the primary prophylaxis group (median age 7.7 years, range 1.2 to 18 years), and 15 in the secondary prophylaxis group (median age 4.7 years, range 1.5 to 14 years). | ‐ 2 children had adverse events associated with endoscopic band ligation prophylaxis: Enterobacter cloacae septicaemia (n = 1) and mild transient upper oesophageal sphincter stenosis (n = 1) |
We did not assess risk of bias in the observational studies as this was not planned.
'Summary of findings' tables
We downgraded the certainty of evidence to very low because of 'within‐trial risk of bias', 'indirectness', and 'imprecision' for the following outcomes: all‐cause mortality; serious adverse events and liver‐related morbidity; and oesophageal variceal bleeding. We could not GRADE the evidence for non‐serious adverse events because no adverse events were reported. Health‐related quality of life was not reported as an outcome (See summary of findings Table 1).
Discussion
Summary of main results
After performing a systematic review of the literature, we found only one abstract describing a paediatric multi‐centre feasibility randomised clinical trial on primary prophylaxis of band ligation versus no active intervention in 22 children with portal hypertension and large oesophageal varices (McKiernan 2011). There was no information about how any of the participants were diagnosed. The trial was at high risk of bias (Figure 3), and the certainty of evidence is very low. Therefore, we are very uncertain whether prophylactic band ligation increases mortality, leads to serious adverse events and liver‐related morbidity, or decreases oesophageal variceal bleeding in children with portal hypertension and large oesophageal varices. The trial abstract did not report non‐serious adverse events related to the intervention. The trial did not include upper gastrointestinal bleeding and quality of life as outcomes. The abstract reported no information on trial funding, and the trial was not subsequently published as a full text. We did not find any other randomised clinical trials for inclusion in this review. Trial data on children with portal vein thrombosis are lacking.
Overall completeness and applicability of evidence
In adults, primary prophylaxis of bleeding varices with variceal band ligation or beta‐blockers is the standard management for people with chronic liver disease and portal hypertension (Garcia‐Tsao 2017). However, there are currently no evidence‐based recommendations for the prophylactic management of children or adolescents at risk of oesophageal variceal bleeding. This is due to a lack of randomised clinical trials (Shneider 2016).
Surveys of paediatric gastroenterologists regarding their use of primary prophylaxis for variceal bleeding in children have shown that they adopt different approaches to the management of children with portal hypertension (Shneider 2004; Gana 2011a; Verdaguer 2016; Jeanniard‐Malet 2017). This suggests that many paediatric specialists apply the guidelines for management of adults with portal hypertension to children.
One possible limitation on conducting randomised clinical trials is the small number of children with portal hypertension compared to adults. However, multi‐centre randomised clinical trials could be conducted. The authors of the included feasibility trial in our review concluded that it was possible to recruit children with portal hypertension for a larger study of primary prophylaxis since prophylactic variceal band ligation was "well tolerated" (McKiernan 2011). We may, therefore, assume the trial authors meant that band ligation may benefit patients.
Different treatments have been proposed for the primary prophylaxis of oesophageal variceal bleeding. This systematic review is one of six reviews that examines the utility of these treatments modalities (Gana 2020; Gana 2019; Gattini 2020a; Gattini 2020b; Cifuentes 2021).
Quality of the evidence
Following the GRADE Working Group grades of evidence, we assessed the measured outcomes in the trial as very low‐certainty evidence, meaning that our confidence in the effect estimate is limited and the true effect may be substantially different from the estimate of the effect. We found no other randomised clinical trials.
Potential biases in the review process
We could not identify any potential bias in the review process. We could not do a funnel plot to assess for possible publication bias since only one trial published as a conference abstract was included.
Agreements and disagreements with other studies or reviews
We found no reviews prepared by other authors on the subject. Other reviews in our suite of reviews compared band ligation versus beta‐blockers (Gana 2019); band ligation versus sclerotherapy (Gana 2020); sclerotherapy versus sham or no intervention (Gattini 2020a); sclerotherapy versus beta‐blockers (Gattini 2020b); and beta‐blockers versus placebo (Cifuentes 2021). The Gattini 2020a review comparing sclerotherapy versus sham or no intervention contains one randomised clinical trial (Gonçalves 2000). However, this is insufficient for the purpose of comparing and discussing results.
Study flow diagram. Date of search 27 April 2020.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1: Band ligation versus sham or no intervention, Outcome 1: All‐cause mortality
Comparison 1: Band ligation versus sham or no intervention, Outcome 2: Serious adverse events and liver‐related morbidity
Comparison 1: Band ligation versus sham or no intervention, Outcome 3: Oesophageal variceal bleeding
| Band ligation versus sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis | ||||||
| Patient or population: children with portal hypertension and large oesophageal varices, without previous gastrointestinal bleeding or beta‐blocker treatment | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with sham or no intervention | Risk with band ligation | |||||
| All‐cause mortality at minimum 6 months* | 0 per 1,000 | 0 per 1,000 | RR 2.54 | 22 | ⊝⊝⊝⊝ | All‐cause mortality was 8% (1/12) in the band ligation group and 0% (0/10) in the no active intervention group |
| Serious adverse events Idiopathic thrombocytopaenic purpura Follow‐up: at minimum 6 months* and Liver‐related morbidity: ‐ liver transplantation | 100 per 1,000 | 28 per 1,000 | RR 0.28 (0.01 to 6.25) | 22 | ⊕⊝⊝⊝ Very low 2 | 0 out of 12 children (0%) in the band ligation group developed idiopathic thrombocytopaenic purpura versus 1 out of 10 (10%) in the no active intervention group. |
| 0 per 1,000 | 0 per 1,000 | RR 2.54 | 22 | ⊕⊝⊝⊝ Very low 2 | 1/12 children (8%) randomised to band ligation underwent liver transplantation while 0/10 children (0%) in the no active intervention group underwent liver transplantation | |
| Health‐related quality of life | Outcome not assessed in the trial | |||||
| Oesophageal variceal bleeding | 300 per 1,000 | 84 per 1,000 | RR 0.28 | 22 | ⊕⊝⊝⊝ | Oesophageal variceal bleeding occurred in 8% (1/12) of the children in the band ligation group and in 30% (3/10) of the children in the no active intervention group. |
| Adverse events considered not serious Follow‐up: at minimum 6 months* | Not assessable | Not reported | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio; RCT: randomised clinical trial; OIS: optimal information size | ||||||
| GRADE Working Group grades of evidence | ||||||
| * Although the trial abstract reported the maximum follow‐up to be two years, it did not specify the time when events occurred for all participants. The trial reported: "All have completed at least six months follow‐up; after the first year the treatment protocol was relaxed to allow fewer variceal band ligation sessions; and 10 have completed the study." 10 children in total seemed to have completed the trial at two‐year follow‐up. 1 Downgraded because of: risk of bias (two levels): blinding of participants and personnel (performance bias) was at high risk of bias, and all other domains were at unclear risk of bias; imprecision (two levels): few events; and the CI of the point estimate is very wide and includes both benefit and harm. 2Downgraded because of: risk of bias (two levels): blinding of participants and personnel (performance bias) was at high risk of bias, and all other domains were at unclear risk of bias; imprecision (two levels): the OIS of 2005 participants was not met; few events; and the CI of the point estimate is very wide and includes both benefit and harm. 3Downgraded because of: risk of bias (two levels): blinding of participants and personnel (performance bias) was at high risk of bias, and all other domains were at unclear risk of bias; imprecision (two levels): the OIS of 540 participants was not met; few events; and the CI of the point estimate includes both benefit and harm. | ||||||
| Study ID | Short summary | Report on harms |
|---|---|---|
| The study assessed primary prophylaxis with endoscopic variceal ligation in 37 children with portal hypertension (22 with liver cirrhosis and 15 with portal vein thrombosis). | ‐ No variceal bleeding occurred during the study period. ‐ No serious adverse events of variceal ligation were reported. The average follow‐up time was 16 months. | |
| The study assessed primary prophylaxis of digestive haemorrhage by oesophageal variceal ligation in comparison to secondary prophylaxis. 30 children were included in the primary prophylaxis group (median age 7.7 years, range 1.2 to 18 years), and 15 in the secondary prophylaxis group (median age 4.7 years, range 1.5 to 14 years). | ‐ 2 children had adverse events associated with endoscopic band ligation prophylaxis: Enterobacter cloacae septicaemia (n = 1) and mild transient upper oesophageal sphincter stenosis (n = 1) |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 All‐cause mortality Show forest plot | 1 | 22 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.54 [0.11, 56.25] |
| 1.2 Serious adverse events and liver‐related morbidity Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.2.1 Idiopathic thrombocytopenic purpura | 1 | 22 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.28 [0.01, 6.25] |
| 1.2.2 Liver transplantation | 1 | 22 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.54 [0.11, 56.25] |
| 1.3 Oesophageal variceal bleeding Show forest plot | 1 | 22 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.28 [0.03, 2.27] |
