1
Global Registry for Outcomes of Varices in Children
(GROOVE)
Protocol Version 1.1
Version date Sept 30, 2013
Principal investigators:
Juan Cristóbal Gana, MD
Division of Paediatrics, Gastroenterology, Hepatology and Nutrition Unit, Pontificia
Universidad Católica de Chile, Chile
Simon C Ling, MBChB
Division of Gastroenterology, Hepatology & Nutrition, The Hospital for Sick Children
and Department of Paediatrics, University of Toronto, Canada
Abbreviations
CPR, clinical prediction rule; CWV, children with varices; EVL, endoscopic variceal
ligation; NSBB, non-selective β-blockers;
GROOVE Protocol, Version 1.1, date Sep 30, 2013
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STUDY SUMMARY
Background & Hypotheses
In children with portal hypertension and esophageal or gastric varices due to liver disease or
portal vein thrombosis (“children with varices”, CWV), we have a poor understanding of the
natural history of varices and the morbidity and mortality associated with gastrointestinal
bleeding. The efficacy of therapies to prevent bleeding in CWV is unknown, in contrast to the
evidence from multiple adult studies that support the evidence-based guidelines for screening
endoscopy and primary prophylaxis with either non-selective β-blockers (NSBB) or endoscopic
variceal ligation (EVL) for adults with cirrhosis. Because a randomized controlled clinical trial
of prophylactic therapy in CWV is not feasible due to the large number of children required for
adequate power, we plan to use the variation in practice among paediatric gastroenterologists and
propensity score methodology to address the following hypotheses:
1. In CWV, prophylactic therapy with non-selective β-blockers (NSBB), endoscopic
variceal ligation (EVL) or endoscopic sclerotherapy (EST) prolongs the time to the first
gastrointestinal bleeding episode compared to no therapy.
2. Gastrointestinal bleeding in CWV can be predicted by a combination of endoscopic,
biochemical, hematological and imaging criteria.
Specific Aims
1. To measure the effect of NSBB, EVL and EST therapies on time to first gastrointestinal
bleed in CWV and to compare their adverse effects.
2. To measure the ability of endoscopic and non-endoscopic criteria to predict
gastrointestinal bleeding in CWV who receive no therapy.
Methodology & Data Analysis
Multiple sites will enroll consecutive children identified to have varices at the time of a clinically
indicated endoscopy. Standard data will be collected at enrollment (including demographics,
details of underlying disease, findings on endoscopy, bloodwork and ultrasound imaging).
Clinical management of the children will be dictated by their gastroenterologist/hepatologist and
will not be specified within the research protocol. Follow-up data will be collected annually,
including details of primary prophylactic therapy. Data will also be collected at the time of
repeat endoscopy, gastrointestinal bleeding, transplantation, portosystemic shunt procedure or
death. We aim to recruit 600 children over 3 years.
For data analysis, children will be divided into two groups. Group 1 (“No therapy group”) will
consist of CWV who receive no prophylactic therapy during follow-up. Group 2 (“Prophylaxis
group”) will consist of CWV who receive prophylactic therapy with any of NSBB, EVL, EST or
combination thereof. The efficacy of NSBB, EVL and EST primary prophylaxis therapy will be
measured by comparison of time to bleeding event using survival analysis and Cox proportional
hazard modelling. To minimize confounding in this non-randomized study design, data from all
groups will be used to specify a propensity score using a logistic regression model in which
treatment assignment is regressed on observed non-endoscopic and endoscopic variables
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measured at baseline and that may influence treatment assignment. .This propensity score will be
included as a variable in the Cox proportional hazard model. Adverse events will be analyzed
using descriptive statistics and survival analysis, where appropriate. We will also undertake
exploratory analyses of the time to first variceal bleed for children receiving NSBB alone and
EVL alone.
The use of endoscopy and non-endoscopic variables to predict variceal bleeding will be analysed
using receiver operator characteristic (ROC) curve methodology and calculation of positive and
negative likelihood ratios.
Significance
The results of this study will provide widely generalizable estimates of the risks associated with
varices, the ability to predict bleeding, and the efficacy of prophylactic therapies in children.
These results will have the potential to radically enhance the current evidence base for the
clinical management of children with varices, enabling generation of clinical guidelines to
improve care and outcomes.
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1.0
BACKGROUND
Prevention and improved management of portal hypertension and its complications in children
are important goals. Portal hypertension and the formation of esophageal varices commonly
accompany advanced liver disease and portal vein thrombosis. Severe and life-threatening
complications may occur, including variceal hemorrhage. Three out of 4 children undergoing
liver transplantation show evidence of portal hypertension prior to transplant, and 1 in 4 have
suffered a major gastrointestinal hemorrhage usually due to rupture of esophageal varices (1).
Unfortunately, there is a paucity of high quality research detailing the natural history and risk for
bleeding in children with varices, and a lack of data to support evidence-based recommendations
for prophylactic therapy to prevent variceal bleeding in children. In contrast, many large-scale
studies in adults with portal hypertension have enabled the implementation of clinical practice
guidelines and improved morbidity and mortality in cirrhotic adults.
1.1
Natural history of esophageal varices
Variceal hemorrhage occurs in children with chronic liver disease or portal vein obstruction (29). In children with biliary atresia, the incidence of variceal hemorrhage ranges from 17% to
29% over a five to 10 year period (4-6) and is 50% in children who survive more than 10 years
without liver transplantation (7). Among 50 children with esophageal varices, primarily due to
cirrhosis, who were prospectively followed and not offered active treatment to prevent variceal
bleeding, 42% suffered upper gastrointestinal hemorrhage during a median 4.5 year follow-up
period (3). For children with extrahepatic portal vein thrombosis, the available studies suggest
that up to 50% suffer a major variceal hemorrhage by 16 years of age (2).
The prevalence of cirrhosis among adults in developed countries ranges between 0.4% and 1.1%
and studies of these patients have led to a greater understanding of the natural history of portal
hypertension in adults than we have for children (10, 11). Gastroesophageal varices are found in
up to two-thirds of cirrhotic adults; those without varices have a 5% chance (12) of developing
varices each year, and 5-10% of those with small varices will progress to large varices each year
(13). Once esophageal varices form, the risk of variceal bleeding within 2 years is between 20%
and 35% (14, 15), and up to 20% of these episodes will be fatal (16).
1.2
Morbidity and mortality associated with variceal bleeding
The mortality rate from gastrointestinal bleeding in children with portal hypertension has been
reported in only a small number of retrospective studies. Overall, mortality ranges from 2.5% to
20%, although children with portal vein thrombosis and bleeding from varices are reported to
have much lower mortality of 0-2% (2-9). There are no prospective studies that have examined
the mortality associated with variceal bleeding in the pediatric population in the context of
modern management approaches.
The morbidity associated with variceal bleeding has not been carefully characterized, although
clinical experience suggests that many children will require admission to an intensive care unit,
and may suffer decompensation of their underlying liver disease, with at least transient
development or exacerbation of ascites and coagulopathy. In cirrhotic adults following variceal
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hemorrhage, studies have quantified the substantial risk of septicemia and renal injury, although
the incidence of these serious complications has not been quantified in CWV.
1.3
Diagnosis of varices
1.3.1
Endoscopy
Endoscopy is considered the gold standard for the diagnosis of esophageal varices (17). Variceal
size can be evaluated endoscopically and correlates with the risk of variceal hemorrhage in adults
(see Section 1.4.1).
1.3.2
Non-invasive diagnosis of esophageal varices
Several studies in adults with cirrhosis have shown that laboratory and imaging measurements
have good predictive power for the non-invasive diagnosis of esophageal varices (18-34). We are
currently undertaking Cochrane systematic reviews to help establish which of these different
approaches offers the greatest non-invasive diagnostic accuracy for esophageal varices (35-39).
Data to support the non-invasive identification of varices in children are sparse. In a recent study
of children with portal hypertension, cirrhotic children with splenomegaly were 14.6 fold more
likely to have esophageal varices compared to cirrhotic children without splenomegaly.
Hypoalbuminemia increased the likelihood of varices (OR 4.17 (95%CI 1.43,12.18)), while the
significance of thrombocytopenia in the univariate analysis did not hold in the multivariable
modeling (40).
Members of our research collaboration have undertaken studies to derive and validate a clinical
prediction rule (CPR) for the non-invasive diagnosis of varices in children. We initially
undertook a retrospective study in 51 consecutive children in one center, in which we derived a
CPR that accurately identified children with varices, using platelet count, spleen size z-score for
age, and albumin (41). We then validated these findings in a prospective multicenter study (42).
Eight centers from Canada, USA, Chile, Israel and UK recruited 108 consecutive children <18y
undergoing endoscopy with a diagnosis of portal hypertension from chronic liver disease or
portal vein obstruction. Based on positive and negative predictive values, the most accurate noninvasive tests for varices were the CPR and platelet count.
1.4
Prediction of variceal bleeding
1.4.1
Endoscopy
Endoscopic characteristics of varices are known to predict future bleeding, including larger
variceal size (43, 44) and the presence of red marks (45-47). Approximately 50-53% of adults
with large varices will bleed and 5-18% of those with small varices will bleed during a 2 year
follow-up period (48, 49). The North Italian Endoscopic Club (50) score, based on clinical and
endoscopic features, has 78% sensitivity, 51% specificity and area under the receiver operating
characteristic curve AUROC of 0.71 to predict variceal bleeding (51). After validation studies of
this score showed worse performance characteristics (52), a revised NIEC score (still reliant on
invasive endoscopy for its variables) was found to have a higher AUROC of 0.8 (53).
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In children with biliary atresia, the risk of bleeding was noted to be higher in those with large
varices, with red marks on the varices (e.g. red spots or red wales), and those in whom
esophageal varices extended beyond the gastro-esophageal junction onto the lesser curvature of
the stomach (54). Children in this study underwent endoscopy at different ages (median 1 year
of age). By 5 years of age bleeding had occurred in approximately 60% of those found to have
grade 2 varices, and 100% of those with grade 3 varices.
Previous attempts to identify predictors of variceal bleeding have focused on adults with
cirrhosis and have used invasive tests (e.g. endoscopy) and/or ultrasound scan or other noninvasive tests (e.g. bloodwork results, Child Pugh score). Ultrasound and Doppler variables,
including portal vein size or the congestion index, have failed to identify reliable thresholds
above which varices develop or bleed (55, 56). Although the congestion index was found to be
correlated with hepatic venous pressure gradient (57), and with the size of varices (58), the
pronounced variability of measures of portal flow within individuals reduces their performance
characteristics as non-invasive tests for the prediction of variceal bleeding. Child Pugh score has
poor sensitivity and specificity for predicting the risk of variceal bleeding (59, 60).
The hepatic venous pressure gradient (HVPG) is an invasive, indirect measure of portal venous
pressure in cirrhosis. A risk of variceal hemorrhage is present when the HVPG is increased
above 12 mmHg (61, 62). Average HVPG is higher in patients who bleed, but a linear
relationship between the HVPG and the risk of bleeding has not been demonstrated (43). Studies
have shown that HVPG measurement in children is safe and suggest that threshold values for
variceal formation and bleeding may be similar to adults (63).
1.4.2
Retrospective pilot study of prediction of esophageal bleeding in children at the
Hospital for Sick Children
The non-invasive CPR for the diagnosis of varices (Section 1.3.2) may also be effective in
identifying children at high risk for variceal bleeding. Clinical, endoscopic and ultrasound
variables and bloodwork results were retrospectively recorded in 40 cases (children who had
bled from esophageal varices) and 34 controls (children with varices, but without bleeding for at
least 1 year following diagnosis) (64). Blood test and imaging data were recorded from 12
months before the bleeding episode. Significant predictors of variceal bleeding were the CPR
(AUROC 0.78, sensitivity 75%, specificity 76%), albumin, collaterals on abdominal ultrasound
and the presence of ascites. The current study will provide an opportunity to validate these
preliminary results within Specific Aim 4.
1.5
Prevention of variceal hemorrhage
Nonselective -blockers (NSBB) and endoscopic variceal ligation (EVL) offer effective primary
prophylaxis (prevention of a first episode of variceal bleeding) in adults with medium or large
varices (65, 66). Guidelines for adult patients in the United States and Europe, based upon
several large clinical trials, recommend endoscopy at the time of diagnosis of cirrhosis and
treatment of those with medium or large varices to prevent bleeding (67-69).
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Due to a lack of controlled studies, the efficacy of primary prophylaxis in children with portal
hypertension remains unclear and the generation of clinical practice guidelines is therefore not
possible (70, 71). Available pediatric data concerning primary prophylaxis are primarily derived
from uncontrolled case series, which are summarized in Table 1 along with the results of the
only published randomized controlled trial of prophylactic endoscopic therapy. This study
compared endoscopic injection sclerotherapy (EST) with no treatment, and reported a benefit of
EST treatment. However, the ability to generalize these results is limited by the very high
bleeding rate in the control group (42%). Furthermore, early studies in adults showed an
unfavourable risk profile for EST and this therapy is therefore not recommended for primary
prophylaxis in adults. However, there are reports of its use for primary prophylaxis in small
infants, for whom the banding apparatus is too large. If undertaken by collaborators in this study,
data on these young infants receiving EST will be captured in Group 4.
Table 1. Studies of primary prophylaxis of variceal bleeding in children.
Beta-blockers
Shashidhar (72)
Ozsoylu (73)
Erkan (74)
EST
Paquet (75)
Howard (76)
Maksoud (77)
Goncalves (3)
Duché (78)
EVL
Cano (79)
Sasaki (80)
Celinska-Cedro
(81)
1.6
Year Design
n
Follow-up
% Bleeding
1999
2000
2003
CS
CS
CS
17
45
10
3y
5y
5.2y
35
16
10
1985
1988
1991
2000
2009
CS
CS
CS
RCT
CS
2
17
26
100
13
10y
2.5y
2.4y
4.5y
8m
0
0
42
6% EST vs 42% control
8
1995
1998
2003
CS
CS
CS
4
9
37
Not given
23m
16m
0
10
0
Developing an evidence base for the appropriate management of children
with varices
Calculations reveal that an adequately powered, controlled clinical trial of prophylactic therapy
with either NSBB or EVL would require recruitment of such a large number of CWV that
complete coverage of the equivalent of 50% of the child population of the USA would be
required (82). Such a large and expensive clinical trial is highly unlikely to ever be achieved.
To overcome this problem, we aim to determine the optimal management to improve outcomes
of CWV using a non-randomized study design and propensity score methodology to minimize
the confounding otherwise inherent to an observational study design.
The principal investigators of this research team have completed several steps towards arriving at
the current proposal. Firstly, we have shown that current practice among paediatric hepatologists
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varies significantly, confirming that quality of care is clearly suboptimal for some children (83).
(84). Secondly, we have undertaken studies to validate a CPR that identifies children at high risk
of varices for whom endoscopy might be indicated (Section 1.3.2) (85). Thirdly, we have pilot
data to suggest that the CPR may also identify children at risk of variceal hemorrhage (Section
1.4.2).
With this current proposal, we now plan to amass prospective data from large numbers of
children with varices diagnosed by endoscopy at numerous centres around the world. We will
utilize the data and the variation in clinical practice to estimate the risk associated with varices,
the ability to predict bleeding, and the efficacy of primary and secondary prophylactic therapies
in children.
2.0
HYPOTHESES AND AIMS
2.1
Hypotheses
1. In CWV, prophylactic therapy with non-selective β-blockers (NSBB),
endoscopic variceal ligation (EVL) or endoscopic sclerotherapy (EST)
reduces the incidence of gastrointestinal bleeding compared to no therapy.
2. Gastrointestinal bleeding in CWV can be predicted by a combination of
endoscopic, biochemical, hematological and imaging criteria.
2.2
Specific Aims
The specific aims of this study are:
1. To measure the effect of NSBB, EVL and EST therapies on time to first
gastrointestinal bleed in CWV and to compare their adverse effects.
2. To compare the ability of endoscopic and non-endoscopic criteria to predict
gastrointestinal bleeding in CWV who receive no therapy.
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3.0
METHODS
3.1
Specific Aim 1:
To measure the effect of NSBB, EVL and EST therapies on time to first
gastrointestinal bleed in CWV and to compare their adverse effects.
3.1.1
Study design
This is a prospective, descriptive, multicenter registry collaboration.
3.1.2
Patients
Participating centres will recruit consecutive children who fulfil all of the inclusion and
exclusion criteria detailed below. Children will be enrolled following a clinically indicated
endoscopy that reveals the presence of varices.
Inclusion criteria

Age 16 years old

Esophageal and/or gastric varices identified by endoscopy.

Presence of
o
EITHER chronic liver disease, defined as liver disease of any etiology and
of any severity, diagnosed by standard clinical assessment and
investigation, that has been present or is expected to persist for at least 6
months,
o
OR portal vein obstruction, defined by standard clinical criteria including
imaging of the portal venous system.

Abdominal ultrasound scan including measurement of spleen length, performed
within 4 months of the endoscopy

Bloodwork including platelet count and albumin, performed within 4 months of
the endoscopy
Exclusion criteria

Previous or current history of upper gastrointestinal bleeding due to portal
hypertension

Previous surgical portal-systemic shunt procedure

Previous insertion of transjugular intrahepatic portal-systemic shunt (TIPS)
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
Previous endoscopic ligation or sclerotherapy of esophageal varices

Current therapy with -blockers, or previous therapy with -blockers within the
last 6 months

Previous organ transplantation

Any current malignant disease

Inability or unwillingness to provide consent for participation in the study.
3.1.3
Patient enrollment
Eligible patients will be initially approached by a member of their healthcare team that is well
known to them, for example their responsible gastroenterologist or hepatologist, or clinic nurse
or nurse practitioner. The approach will be made prior to the endoscopy being undertaken, either
when the decision is made to book the procedure, or on the day of the procedure. Verbal and
written information will be provided to the patient (as age appropriate) and family, and informed
consent obtained. Children without capacity to consent but with the ability to understand the
assent form will be asked to provide their assent.
3.1.4
Schedule of assessments
Data collection will occur at baseline (time of the endoscopy) and at the annual anniversaries of
the endoscopy. Initial data analysis will be based on 2 years of follow-up, but data collection is
expected to continue long-term thereafter, with an appropriately modified and approved protocol,
to maximize the opportunities for use of this unique registry data. Evaluations undertaken at each
time-point are detailed in Section 2.6 and in Table 2.
Table 2. Timetable of patient evaluations.
Enrollment
Annual
follow-up
Background data
X
(page 19)
X
(page 26)
Endoscopy data
form (Page 23)
X
Ultrasound data
form
X
X
Bloodwork
X
X
Bleeding event
data form (page
25)
At time of At time of
clinically a bleeding
indicated
event
endoscop
y
X
At
identification
of an
endpoint*
X
X
X
X
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Endpoint data
form (Page 29)
X
*Death, portosystemic shunt surgery, meso-Rex bypass surgery, TIPS or liver transplantation
3.1.5
Measurements
Baseline data
The following information will be obtained at baseline, coinciding with or within 4 months of the
initial endoscopy: background information, which includes demographic information, primary
diagnoses, comorbidities, medications, and details of physical examination. Laboratory tests,
abdominal ultrasound scan, disease severity scores (Child Pugh, the Model for End-stage Liver
Disease (MELD) or the Pediatric End-stage Liver Disease (PELD) scores (87-89)). Data
collected from the endoscopy will include presence and location of varices, variceal size, red
marks, and presence of gastropathy (see Section 2.6.3 below).
Annual follow-up data
Follow-up data to be collected annually thereafter includes clinical history (including details of
bleeding episodes (Section 2.6.5), date of and indication for liver transplantation, or date of
death), physical examination, therapies (medications, endoscopic therapy, surgical therapy) (see
Section 2.6.4), and standard bloodwork variables from bloodwork performed as part of routine
clinical care (Appendix 1).
If repeat endoscopy and/or repeat USS are performed for clinical indications, details will be
recorded for the study, along with the bloodwork results from the nearest time-point available
within 4 months of these investigations.
Endoscopic data
The appearances of esophageal varices will be scored by the endoscopist according to the
systems detailed below. In addition, a pictorial record of the endoscopy will be provided either
by video or by multiple endoscopic pictures (including with and without air insufflation),
according to the capabilities of each centre to capture endoscopic video. This record of the
endoscopy will be independently and blindly reviewed by two additional endoscopists from other
centres, who will grade the varices blinded to the results of other tests including abdominal
ultrasound scan and bloodwork results. Scores obtained in these ways will be compared and
interobserver variability will be calculated. In case of discrepancies, the final scoring will be
resolved by majority. Endoscopists who review images will undergo training and periodic
assessment using standardized videos and pictures to ensure uniformity of scoring is maintained
throughout the study.
The presence and appearance of esophageal varices will be recorded. Variceal size will be
graded according to the following scoring system:
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A previously evaluated semiquantitative grading (90, 91) based on two criteria; flattening of
esophageal varices by insufflation of air, and confluence of adjacent varices around the
esophageal wall. Three grades are possible:
a) Small varices: flatten with air insufflation and not confluent around the esophageal
wall.
b) Medium varices: do not flatten with air insufflation and not confluent around the
esophageal wall.
c) Large varices: do not flatten with air insufflation and are confluent around the
esophageal wall.
This semi-quantitative approach was chosen because is the best validated of all variceal sizing
system and it provides better inter-observer agreement as compared with quantitative grading
(92).
In addition, note will be made of the presence of vein-on-vein (also called red wales) or red
spots. Gastric or duodenal varices will be noted and described. Edema, submucosal petechial
areas, and snake-skin appearance of the stomach will be described to be consistent with portal
hypertensive gastropathy.
Treatment
Primary prophylaxis of variceal hemorrhage by endoscopic banding ligation or oral -blocker
therapy will be offered to patients at the discretion of the local clinician in each centre and not
determined by this research protocol.
Dosing of NSBB will be recorded. Number of episodes of EVL and the details of each
procedure will be recorded.
Gastrointestinal bleeding episodes
Details of gastrointestinal bleeding episodes will be collected, including date, markers of severity
(e.g. presence of hemodynamic disturbance, lowest haemoglobin, administration of blood
products), and subsequent comorbidities (e.g. infection, ascites, encephalopathy, admission to
critical care unit, rebleeding) or death.
3.1.6
Sample size
Previously published data do not support a sample size calculation for this study design.
Therefore, we aim to recruit as many patients as possible. We expect to ultimately include up to
60 sites (in a step-wise fashion, with the final number of sites determined by the recruitment
rate). With average recruitment per site of 10 patients, we will achieve a sample size of 600 over
a recruitment period of 3 years.
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3.1.7
Analysis
For data analysis, children will be divided into two groups. Group 1 (“No Therapy Group”) will
consist of CWV who receive no prophylactic therapy during follow-up. Group 2 (“Prophylaxis
Group”) will consist of CWV who receive prophylactic therapy with any of NSBB, EVL, EST or
combination thereof.
Baseline data from Groups 1 and 2 will be used to describe the proportions of patients with each
different grade of varices. Demographic and clinical data will be described using means and
standard deviations, medians with interquartile range, and proportions (with 95% confidence
interval), as appropriate. Data from Group 1 will be used to describe the incidence of and time to
gastrointestinal bleeding in CWV who receive no prophylactic therapy, the incidence and nature
of associated morbidity, and the associated mortality. Two survival curves will be presented, one
for children with parenchymal liver disease and another for children with portal vein obstruction.
In this observational study, subjects receiving different prophylactic treatments may differ
systematically from untreated subjects, because treatment is offered based primarily on the usual
practice of the treating physician. This differs from a randomized controlled trial (RCT), in
which treatment allocation is random. The use of a propensity score allows the design and
analysis of an observational study to mimic some of the characteristics of a randomized study.
Conditional upon the propensity score, the distribution of observed baseline covariates will be
similar between groups of treated and untreated subjects (93). Thus, just as randomization would
result in measured and unmeasured baseline variables being balanced between treatment groups,
so conditioning on the propensity score will, on average, result in measured (but not necessarily
unmeasured) baseline covariates being balanced between treatment groups (94). Furthermore,
propensity score methodology allows estimates of treatment effects to be presented in ways
similar to RCTs, for example the use of hazard ratios and number-needed-to-treat.
In this study, the propensity score will be specified using a logistic regression model that
includes the baseline variables that are considered to be potential confounders, as they may
influence treatment allocation by the treating physician (Table 3). An iterative approach will be
used, as recommended by experts in this methodology (93, 95). An initial propensity score
model will be specified and the comparability of treated and untreated groups of subjects will be
assessed using this initial score. If important systematic differences remain, the initial score will
be modified. Potential modifications include addition of covariates to the model, addition of
interactions between covariates, or modeling of the relationship between covariates and
treatment status using non-linear terms. This approach will be repeated until systematic
differences between groups are reduced to an acceptable level.
Table 3. Variables that may be predictive of outcome (variceal bleeding), decision to provide
prophylactic treatment, or both, for inclusion in the initial iteration of the propensity score
Non-endoscopic variables
Endoscopic variables
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Predictive of outcome and decision to treat
CPR
Platelet count
Spleen size for age z-score (SSAZ)
Platelet/SSAZ ratio
Albumin
INR
Total and conjugated bilirubin
AST/ALT ratio
Child Pugh score
PELD or MELD score
Diagnosis
Weight-for-age Z-score
Height-for-age Z-score
Age
Time from diagnosis of portal hypertension
Grade of varices
Red marks on varices
Gastric varices
Portal gastropathy
Predictive of decision to treat
Centre
Data from patients in Groups 1 and 2 will then be used to estimate the treatment effect of any
prophylactic therapy compared to no treatment, using the propensity score to balance baseline
variables. The propensity score will be incorporated into the data analysis by a method called
inverse probability of treatment weighting (IPTW) using the propensity score (93). Outcomes
will be analyzed by Cox regression model with the propensity score as a variable within the
model.
The efficacy of prophylactic therapy will be analyzed in two ways:
(a) Survival analysis controlling for propensity score using a Cox proportional hazard model.
(b) Proportions in each group who bleed during a fixed follow-up period, controlling for
propensity score.
We will minimize the effect of “immortal time bias” (also known as “survivor treatment bias”)
by asking investigators to specify their intended therapy at the time of the endoscopy. We will
then conduct an “intention to treat” analysis based on this declared therapy, using the time of
endoscopy as the starting point of follow-up, even if therapy was not commenced until some
time thereafter. This delay in commencement of therapy is expected to be most important for
treatment with beta-blockers (96).
3.1.7.1 Exploratory analyses
We will also undertake exploratory analyses to estimate the treatment effect of NSBB alone,
EVL alone, and combination therapy with NSBB and EVL, compared to no treatment. The
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propensity score will again be used to balance baseline variables. We will use survival analysis
and a Cox proportional hazards model.
3.2
Specific Aim 2:
To measure the ability of endoscopic and non-endoscopic criteria to predict
gastrointestinal bleeding in CWV who receive no therapy.
Data from Group 1 will be used to address this aim. Children within Group 1 will be divided into
those who have bled and those who have not bled, and separate analyses will be performed for
the groups of children with portal hypertension due to parenchymal liver disease and those due to
portal vein obstruction. It is recognized that the timing of recruitment to this study is not
necessarily at the onset of the presence of varices, but occurs instead at a variable point in the
natural history of the varices dependent upon the timing of endoscopy in clinical care. Timing of
endoscopy may vary between centres and physicians. Any tendency for the study entry criteria
to select for the sicker patients will be balanced between treatment groups by inclusion in the
propensity score of baseline variables that measure disease severity. In addition, data will be
collected to provide an estimate of the duration of liver disease and the duration of portal
hypertension (for example, date of onset of splenomegaly), when such information is available,
for use in exploratory sensitivity analyses.
First, data will be explored to search for variables that differ across these two groups. Variables
known to be predictive of the presence of varices and suggested by our pilot study to be
predictive of bleeding will be included in this initial analysis (Table 3).
Continuous variables (such as age, disease duration, laboratory values and spleen size) will be
compared using Student’s t test or Wilcoxon rank sum test, as appropriate for the data normality.
Categorical variables (such as gender, presence of cirrhosis and comorbidity) will be compared
using χ2 test or Fisher’s exact, as appropriate. It is to be emphasized that these analyses will be
exploratory in nature and will not affect the primary analysis. Therefore, no correction is planned
for multiple comparisons and a P value of <0.05 will be considered statistically significant.
The primary analysis for this specific aim will use diagnostic utility methods to evaluate the
ability of CPR to predict bleeding within 1 year and, in a separate analysis, within 3 years of
enrollment. Receiver operator characteristic (ROC) curve will be constructed, reporting the area
under the curve (AUC) with the corresponding 95%CI. Area under the ROC curve of over 0.7
will be considered indicative of a ‘fair’ test, 0.8 as ‘good’, and over 0.9 as an ‘excellent’ test. The
optimal cutoff of the CPR score will be determined as the point at which the second diagonal
crosses the ROC curve (i.e. the point where the shoulder of the curve is closest to the left upper
side of the figure). Other cutoffs to maximize sensitivity or specificity will be also explored.
Sensitivity, specificity, predictive values, and likelihood ratios will be calculated for this optimal
cutoff score, and two others, one to aim at optimizing sensitivity and the other to optimize
specificity.
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16
Exploratory analyses will be undertaken using a similar diagnostic utility statistics approach to
examine other test variables, such as spleen size, platelet count, and the ratio between AST and
ALT. Discussion of the best prediction rule will follow visual inspection of the various area
under the ROC curve values, prediction values and feasibility.
4.0
GENERAL CONSIDERATIONS
4.1
Ethics
Each participating centre will obtain approval from their local Institutional Review Board,
Research Ethics Committee, or similar body. The study will be conducted in adherence to ethical
principles of medical research outlined in the Declaration of Helsinki and other relevant
documents.
4.2
Privacy
All data submitted to the study database, or kept locally in each collaborating centre, will be deidentified. Participants will each receive a unique identifying number that will appear on all their
documentation. No potential identifiers will be collected, including initials, full date of birth (we
will collect month and year only), or postal code.
The online database will be password-protected, and each collaborator will have their own
unique username and password. Documentation held at local sites will also be held in passwordprotected files, drives and/or computers. Paper copies of research data will be kept in locked
drawers in locked offices to which only members of the research team will have access.
4.3
Data-transfer agreements
Each collaborating centre will sign a data transfer agreement with Pontificia Universidad
Católica de Chile according to the requirements of the local regulatory authorities.
GROOVE Protocol, Version 1.1, date Sep 30, 2013
17
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