Alimentary TractRacecadotril for childhood gastroenteritis: an individual patient data meta-analysis
Introduction
Acute gastroenteritis (AGE) is a very common disorder, particularly in emerging countries, where it constitutes one of the major health complications for infants and young children. Amongst the causes of death in children under five in the world, diarrhoeal diseases are still the second cause with 16%, just after the acute respiratory infections [1].
Oral rehydration solution is the cornerstone of AGE therapy to prevent and cure dehydration that dominates the prognosis, following miscellaneous guidelines [2], [3], [4], [5], [6], [7], [8]. In addition to this standard reference therapy, an adjuvant medication might prove useful insofar as it is safe and reduces dehydration duration and accelerates return to normal state. The efficacy of these adjuncts in combination with oral rehydration solution has been recently studied: probiotics [9], [10] such as lactobacilli or some yeasts (Saccharomyces boulardii), smectite [11] and racecadotril [12].
Racecadotril prolongs endogenous enkephalin action by inhibiting enkephalinase at the intestinal level, and thus, increases their intestinal antihypersecretory effect [13], [14], [15]. Its efficacy in infants and children suffering from AGE has been assessed in various clinical randomised trials (RCTs) [16], [17], [18], [19], [20], [21], [22], [23], [24], [25].
These trials differed in duration, selection of efficacy endpoints, and were conducted in different countries with various cultural contexts. Systematic reviews were reported in recent years [12], [26], [27], [28], [29], [30], [31]. However, (a) these reviews only included a small part of existing trials, (b) the treatment effect was estimated by meta-analyses from literature (MAL) in pooling different endpoints, such as duration of diarrhoea, symptoms sum scores, and stool output into unitless effect size obscuring the clinical interpretation, (c) the suspected strong influence of baseline conditions (dehydration level, Rotavirus, etc.) was never investigated. The treatment overall efficacy was never adjusted for these variables and whether efficacy remains constant depending on baseline conditions was never questioned [32], [33].
We evaluated the effectiveness of racecadotril compared with placebo in collecting the largest number of trials and taking advantage of Individual Patient raw Data (IPD) in four main purposes: (a) to homogenise the calculation of the studied endpoints with the same definition across trials, (b) to identify the baseline predictors of oral rehydration solution therapy response out of consideration of treatment, (c) to assess the overall racecadotril + oral rehydration solution efficacy compared with oral rehydration solution alone, in adjusting for relevant baseline conditions, and (d) testing the invariance of this efficacy to baseline severity conditions and possible responder sub-groups. Racecadotril safety was investigated elsewhere [34] and not of concern in this work.
Section snippets
Eligibility criteria
We included all the RCTs where at least racecadotril and placebo were randomised, without restriction on language or publication, and characterised by an acceptable methodological quality (defined as a Chalmers Score [37] >50).
Participants: Infants and children, from 1 month to 15 years old, male or female, of any ethnic group, suffering from AGE, whatever the presumed origin.
Interventions: Oral rehydration solution in combination with racecadotril sachets, whatever dosage or duration treatment
Study selection
We found a total of 69 documents relating nine distinct RCTs (Table 1). RCTs were based placebo controlled [16], [17], [18], [22], excepted Cojocaru et al. [19] and Melendez Garcia and Rodriguez [23] (using kaolin-pectin as control treatment), and Santos et al. [20] and Alvarez-Calatayud et al. [21] (oral rehydration solution alone). The excluded (essentially observational) studies are listed in Table 2. The raw data were found available for all selected trials, and all the authors agreed to
Discussion
This sample of 1384 patients based on nine RCTs constitutes the first individual patient data meta-analysis related on oral rehydration solution adjuncts in childhood acute gastroenteritis, and gathers the largest number of trials and patients on existing racecadotril meta-analyses. These data are coming from several countries with different cultures: India, Peru, Guatemala, Spain, France and Mexico. Obvious heterogeneities were found between data in terms of inclusion criteria, type of
Limitations
Although clinical evidence of the efficacy of racecadotril added to oral rehydration solution is provided in this analysis, the economic utility of this compound remains to be demonstrated. Such an objective requires a much more important data collection task, including accounting of medical resources, need of care, especially the need of i.v. rehydration and hospitalisation.
The efficacy of racecadotril was shown independent of age; however this data collection only concerns infants, toddlers
Conclusions
Our data have gathered a variety of baseline conditions and cultural contexts and constitutes a large data base collected at individual patient level to assess the effects of adjunct treatment to oral rehydration solution in child acute gastroenteritis.
A predictive model of recovery was invariably identified based on only two variables: dehydration level and Rotavirus. This model remained constant over all the other baseline variables and all the cultural groups.
Racecadotril was found with a
Conflict of interest statement
None declared.
Acknowledgements
This research project would not have been possible without the unconditional support of all the investigators. We are indebted to Dr Salazar-Lindo for his continuous support to this study. We also express our gratitude to Professor Hania Szajewska, (University of Warsaw) for her relevant comments.
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