Selective vasopressin type 2 receptor antagonist for patients with cirrhosis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the benefits and harms of selective vasopressin type 2 receptor antagonist drugs for patients with cirrhosis and ascites.
Background
Description of the condition
Ascites is a common complication observed in patients with liver cirrhosis. This complication is reported in about 50% of compensated cirrhosis patients over a 10‐year observational period. Ascies is the initial symptom of the disease in 15% of the patients (Ginés 1987). It is a common cause of decompensation in hospitalised patients (Planas 2006) and cause‐increased mortality in this clinical setting. The mortality at one month, six months, and one year, is 22%, 40%, and 48%, respectively (Khan 2009). Ascites is one of the prognostic factors for developing other cirrhosis‐related liver complications such as variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatocellular carcinoma (Kim 2008).
The pathogenic mechanism is characterised by increased pressure in the portal system, vasodilation, increased extravasation of fluid from the splanchnic microcirculation, and disturbances in the liquid reabsorption by terminal lymphatics located in the diaphragm (Akay 2008). Vasodilatation and fluid loss leads to a hyperdynamic circulation with effective arterial hypovolaemia, which activates the renin–angiotensin–aldosterone system, sympathetic nervous system, and vasopressin system (Cazzaniga 2008). These events result in increased renal water and sodium retention, increasing the ascites and perpetuating the impaired free‐water excretion (Martin 1997; Porcel 2002).
Description of the intervention
The management of ascites includes sodium restriction, use of diuretics, paracentesis, and transjugular portosystemic shunt (TIPS). These interventions are indicated according to the magnitude, the difficulty to evacuate the fluid, and how easy the ascites is produced. These reasons explain why in some cases it is not possible to obtain an adequate outcome, such as in patients in which ascites fails to be mobilised; or in cases of early recurrence after paracentesis refractory to medical therapy. The refractoriness is classified in two groups: a) diuretic‐resistant ascites, characterised by poor response to sodium restriction and diuretic treatment; and b) diuretic‐intractable ascites, characterised by diuretic‐induced complications that preclude further use of an effective diuretic dosage. Usually 10% of patients with ascites are classified as refractory to treatment. In these patients management is based on serial therapeutic paracentesis, TIPS, peritoneovenous shunt, or liver transplantation (EASL 2010). The presence of adverse events secondary to diuretic therapy is common in clinical practice including electrolyte disturbances, hyperkalaemia, leukopenia, thrombocytopenia, malaise, gastrointestinal disturbances and drowsiness, rashes, and abnormal hepatic and renal function (McKenna 2010).
Aquaretics, such as VPA‐985 (lixivaptan), satavaptan, tolvaptan, and RWJ‐351647, are inhibitors of the vasopressin type‐2 receptors (V2R), acting at the renal tubular level to induce water‐loss and sodium retention, representing a potentially new therapeutic option for patients with ascites refractory to standard treatment (Manning 2008).
How the intervention might work
V2R are expressed in the epithelium of the renal collecting tubule, mediating the osmotic effects of vasopressin (Rihakova 2006) through the insertion of preformed aquaporin‐2 molecules in the luminal membrane of principal cells, allowing water reabsorption. V2R‐antagonist also has a natriuretic effect, which is thought to derive from the inhibition of endogenous V2R‐mediated stimulation of epithelial sodium channels and by an increase in endogenous vasopressin levels (Perucca 2006). V2R‐antagonists exhibit high efficacy as aquaretics for patients with heart failure and hepatorenal syndrome with inappropriate secretion of vasopressin (Rihakova 2006).
Satavaptan inhibits vasopressin by binding to the V2R in membrane‐preparation of human kidney. Satavaptan is well absorbed; the reported half‐life is near to 14 to17 hours. Maximal plasma concentrations are observed three hours after dosing; mean plasma concentration increased with dosage and duration of drug administration and is stabilised after five days of treatment. Patients receiving drugs which induce Cytochrome P450 3A4 (CYP3A) had lower plasma levels. The major route of excretion is via faeces (Costello‐Boerrigter 2009).
There is clinical evidence suggesting high plasma vasopressin concentrations in patients with advanced cirrhosis. These elevated concentrations are due to vasodilatation and a reduced effective intravascular volume. High plasma vasopressin concentrations and decreased glomerular filtration rate are the two most important factors implicated in the enhanced water retention, observed in near in 75% of in‐hospital patients with ascites (Ferguson 2003). V2R‐antagonists could be beneficial in the treatment of patients with ascites inducing an effective aquaresis and block V2‐mediated vasodilatation. The beneficial effects in water excretion may provide a potential therapy for patients with resistant ascites (Ferguson 2003).
Why it is important to do this review
These new pharmacological alternatives seem attractive and offer a plausible physiologic basis which could be turned into patient relevant outcomes. We could not find a meta‐analysis nor a systematic review on V2R‐antagonists for patients with ascites and liver cirrhosis.
Objectives
To assess the benefits and harms of selective vasopressin type 2 receptor antagonist drugs for patients with cirrhosis and ascites.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised clinical trials comparing different types of selective vasopressin V2R antagonist drugs against no intervention, placebo, or another intervention to manage ascites as diuretics, paracentesis, TIPS or surgical procedures, in patients with cirrhosis and ascites. We will include trials irrespective of publication status, year of publication, or language. Blinding in the trials will not be required as it would have been difficult to perform on patients undergoing invasive procedures.
Non‐randomised studies that may come up with the search will be included for the report of harm only.
Types of participants
We will include adult patients diagnosed with cirrhosis and ascites due to portal hypertension, regardless of the aetiology of cirrhosis or severity of the ascites. The diagnosis of liver disease will be made on a combination of biochemical and clinical data.
Types of interventions
Any selective V2R‐antagonist drugs versus no intervention, placebo, or other interventions for management of ascites.
We will consider the following interventions for management of ascites: sodium restriction, diuretics, paracentesis, TIPS, or surgical procedures (eg, peritoneovenous shunt).
Types of outcome measures
Primary outcomes
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All‐cause mortality;
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Disease‐specific mortality (mortality secondary to complications of liver cirrhosis) or liver transplantation;
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Adverse events: Number of participants with serious adverse events defined as "any untoward medical occurrence that at any dose results in death, is life‐threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity". All other adverse events will be considered non‐serious (ICH‐GCP 1997).
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Quality of life score (measured by any scale) between groups.
Secondary outcomes
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24 hr urinary flow.
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Re‐accumulation of ascites.
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Number of paracentesis.
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Body weight.
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Hepatic encephalopathy.
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Glomerular filtration rate.
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Serum sodium levels.
Search methods for identification of studies
Electronic searches
Relevant randomised trials will be identified by searching The Cochrane Hepato‐Biliary Group Controlled Trials Register (Gluud 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index EXPANDED (Royle 2003).
Search strategies and time span of the searches are reported in Appendix 1.
Searching other resources
The references of all identified studies will be inspected for more trials. Additionally, the first or corresponding author of each included trial, as well as researchers active in the field, will be contacted for information regarding unpublished trials and complementary information on their own trial.
Data collection and analysis
Selection of studies
Two review authors (NC and FT), independently of one another, will inspect each identified reference and will apply the inclusion criteria. For potentially relevant articles, or in cases of disagreement between the two reviewers, the full text article will be obtained and inspected independently. If resolving disagreement by discussion will not be possible, the publication will be added to those 'awaiting assessment', and the authors of the original study will be contacted for clarification. In the event of no reply from the authors within three months, a third review author (MU or NMS) will review the article to solve the disagreement. Justification for study exclusion will be documented.
Data extraction and management
Two review authors (NC and TB), independently of one another, will extract the data from the included trials. In case of disagreement between the two authors, a third review author (FT) will extract the data. The data extraction will be discussed, decisions documented, and, when necessary, the authors of the original studies will be contacted for clarification. Justification for study exclusion will be documented. Trials will be identified with the last name of the first author and the year in which the trial was first published, and will be ordered chronologically.
The following data will be extracted, verified, and recorded:
Characteristics of trials
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Date, location, and setting of trial.
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Publication status.
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Definitions used (no refractory and refractory ascites).
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Sponsor of trial (known or unknown; industry or not industry).
Characteristics of participants
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Number of participants in each group.
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Age, sex, nationality.
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Severity of liver disease and cirrhosis according to the aetiology of liver disease, regardless of the criteria used.
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Presence of other liver‐relate complications.
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Degree of renal dysfunction as determined by serum creatinine.
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Previous use of diuretics or paracentesis for ascites management.
Characteristics of interventions
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Type of V2R antagonist, dose, mode of administration, schedule, length of follow‐up (in days).
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Number of days that vasopressin V2R antagonist was provided.
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Use of diuretics, paracentesis, TIPS or peritoneovenous shunt for ascites management.
Characteristics of outcome measures
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Whenever possible, the number of events previously listed under Types of outcome measures will be recorded in each group of the randomised trials.
Assessment of risk of bias in included studies
Two authors (NC and TB) independently will assess bias risk of the trials, without masking the trial names. For this purpose, instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and the Cochrane Hepato‐Biliary Group Module (Gluud 2011) will be followed.
Sequence generation
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Low risk of bias, if the allocation sequence was generated by a computer or random number table. Drawing of lots, tossing of a coin, shuffling of cards, or throwing dice were also considered as adequate if a person who was not otherwise involved in the recruitment of participants performed the procedure.
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Unclear, if the trial was described as randomised, but the method used for the allocation sequence generation was not described or insufficient to permit judgement.
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High risk of bias, if a system involving dates, names, or admittance numbers were used for the allocation of patients.
Allocation concealment
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Low risk of bias, if the allocation of patients involved a central independent unit, on‐site locked computer, identically appearing numbered drug bottles or containers prepared by an independent pharmacist or investigator, or sealed envelopes.
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Unclear, if the trial was described as randomised, but the method used to conceal the allocation was not described or insufficient to permit judgement.
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High risk of bias, if the allocation sequence was known to the investigators who assigned participants or if the study was quasi‐randomised in case of employment of a valid placebo.
Blinding of participants, personnel, and outcome assessors
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Low risk of bias (blinding was performed adequately, or the outcome measurement is not likely to be influenced by lack of blinding).
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Uncertain risk of bias (there is insufficient information to assess whether the type of blinding used is likely to induce bias on the estimate of effect).
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High risk of bias (no blinding or incomplete blinding, and the outcome or the outcome measurement is likely to be influenced by lack of blinding).
Incomplete outcome data
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Low risk of bias (the underlying reasons for missingness are unlikely to make treatment effects departure from plausible values, or proper methods have been employed to handle missing data).
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Uncertain risk of bias (there is insufficient information to assess whether the missing data mechanism in combination with the method used to handle missing data is likely to induce bias on the estimate of effect).
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High risk of bias (the crude estimate of effects (eg, complete patient estimate) will clearly be biased due to the underlying reasons for missingness, and the methods used to handle missing data are unsatisfactory).
Selective outcome reporting
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Low risk of bias, considering that most of the included trials were made before of the obligatory registration on randomised clinical trials databases, and the pre‐specified outcomes are not available. The following outcomes were considered fundamental as outcome to avoid selective reporting; a) mortality, b) response rate, and c) adverse events.
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Unclear, there is insufficient information to assess whether the magnitude and direction of the observed effect is related to selective outcome reporting.
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High risk of bias, not all of the trial's pre‐specified primary outcomes have been reported or similar.
Vested interest bias
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Low risk of bias, if the trial's source(s) of funding did not come from any parties that might have conflicting interests (eg, a V2R antagonist manufacturer), or if any academic, professional, financial, or other benefits to the person responsible for the trial are independent of the direction or statistical significance of the trial results.
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Unclear, if the source of funding was not clear, or if it is unclear if the person responsible for the trial stands to benefit according to the direction or statistical significance of the trial results.
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High risk of bias, if the trial's source of funding had a conflict of interest, or if any academic, professional, financial, or other benefits to the person responsible for the trial are dependent of the direction or statistical significance of the trial results.
All trials will be assessed for risk of bias. If the risk of bias in a trial is judged as 'low' in all the listed above domains, the trial will fall in the 'low risk of bias' group trials. If the risk of bias is judged as 'uncertain' or 'high', then the trial will fall in the group with 'high risk of bias'.
Furthermore, we will register whether or not the randomised clinical trials used 'intention‐to‐treat' analysis (Gluud 2011), the length of follow‐up, and sample size calculation. Any disagreement will be resolved by discussion and settled by a third author (MU or NMS). We will contact the trial author for clarification as necessary.
We will assess the quality of evidence also at the outcome level across trials using the GRADE approach; the first three primary outcomes will be included in the summary of findings table (GRADE table) (http://ims.cochrane.org/revman/other‐resources/gradepro).
Measures of treatment effect
Dichotomous data will be analysed calculating the relative risk (RR) for each trial, expressing the uncertainty with 95% confidence intervals (CI). Continuous data will be analysed calculating mean differences (MD) between groups of each trial and its 95% CI. Comparisons will be made between trials evaluating V2R antagonist against no intervention, placebo, or other interventions.
Unit of analysis issues
The trials will be explored to identify variations in the randomisation process. The preferable design will be simple parallel group. However, other design as cluster randomised trials, cross‐over trials, and repeated measurements during the trial will be analysed in detail, and we will follow the guide from the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Dealing with missing data
In order to examine the influence of drop‐outs, we will perform both worst‐best patient scenario analysis (assigning bad outcomes to all of the missing experimental group patients and good outcomes to all of the missing control group patients) and best‐worst patient scenario (assigning good outcomes to all of the missing experimental group patients and bad outcomes to all of the missing control group patients) analysis.
Assessment of heterogeneity
We will check the heterogeneity of effects across trials by visual inspection of the forest plots and Chi2 and I2 tests for heterogeneity (Higgins 2011). Statistical heterogeneity will be defined as a P value > 0.10 (Chi2) or I2 > 25%. When heterogeneity exists, subgroup analyses will be performed in order to assess the impact of potential sources of heterogeneity over the main results.
Assessment of reporting biases
A funnel plot estimating the precision of trials (plot of logarithm of the RR against the sample size) will be used to estimate potential asymmetry. In addition, the standard normal deviate (SND), defined as the RR divided by its standard error, will be regressed against the estimate's precision (regression equation: SND = a + b x precision) in order to facilitate the prediction of potential heterogeneity or data irregularities in the meta‐analyses (Egger 1997). In this equation, the SND reflects the degree of funnel plot asymmetry as measured by the intercept from the regression analysis.
Data synthesis
For the statistical analyses, we will use RevMan Analyses (RevMan 2011). Dichotomous data were will be synthesised poling the RR and 95% CI from all trials to estimate the global effect of the intervention. Continous data will be synthesised using MD and 95% CI from each trial to calculate the average mean difference.
Trial sequential analysis
In order to control for the risks of random errors due to sparse data and multiplicity in cumulative meta‐analysis, we will perform trial sequential analysis (Brok 2008; Wetterslev 2008; Thorlund 2009). The programme is available at http://ctu.dk/tsa. We will calculate the required information size (ie, the number of participants needed in a meta‐analysis to detect or reject a certain intervention effect) (Wetterslev 2008). In our analysis, the required information size will be based on the minimal relevant difference of a half standard deviation of the meta‐analysis, the standard deviation of the meta‐analysis, a type I error of 5%, and a type II error of 20% (Wetterslev 2008). As default, diversity adjusted required information size will be used unless otherwise stated (Wetterslev 2008; Wetterslev 2009).
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 will add the trials according to the year of publication, and if more than one trial was published in a year, trials will be added alphabetically according to the last name of the first author (Wetterslev 2008).
On the basis of the required information size, trial sequential monitoring boundaries will be constructed (Wetterslev 2008). 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 is crossed before the required information size is reached, firm evidence may be established and further trials may turn out to be superfluous. On the other hand, if the boundary is not surpassed, it is most probably necessary to continue doing trials in order to detect or reject a certain intervention effect.
Subgroup analysis and investigation of heterogeneity
In case of significant heterogeneity, the possible sources will be analysed and sub‐group analysis will be done to identify the sources of heterogeneity.
Sensitivity analysis
We will analyse the data using both fixed‐effect and random‐effects model meta‐analyses. When both models produce similar estimates, the fixed‐effect result will be reported; otherwise, we will report the results from both analyses. Outcomes will be analysed as reported in the trial, ie, either per protocol or as intention‐to‐treat analysis.
