19 PIDSP Journal 2010 Vol 11 No.2 Copyright ® 2010

RACECADOTRIL IN THE TREATMENT OF ACUTE DIARRHEA IN CHILDREN: A META-ANALYSIS

AUTHORS : Robina Hao, M.D. *, Michelle De Vera, M.D. *, Emily Resurreccion, M.D.* The Medical City, Ortigas Ave., Pasig City 3rd Place Winner, Poster Research Contest at the 17 th Annual PIDSP Convention, 2010

KEYWORDS diarrhea, racecadotril

ABSTRACT

Diarrhea has been the subject of considerable attention and effort. A variety of anti-secretory agents have been subjected to countless investigations including racecadotril as an adjunct therapy. Objectives: To assess the effectiveness of racecadotril, along with oral rehydration solution, in the treatment of diarrhea. Methods: The Cochrane Library and Pubmed were searched for trials; high sensitive search terms were used including “randomized controlled trials”, “racecadotril” and “diarrhea”. Outcome measures were stool output, duration of diarrhea, and number of bowel movements. Data Collection and Analysis : Three reviewers assessed the methodological quality. Analysis was implemented with Review Manager 5 using standard mean difference as treatment measure. Results: The search yielded 21 results; four of which fulfilled selection criteria. A total of 659 participants were given 1.5mg/kg of racecadotril. The meta-analysis showed that racecadotril is effective in reducing stool output in 48 hours compared to the control group. This finding was congruent for those positive for rotavirus and for the duration of the diarrhea. There were lesser children who revisited their doctors after 48 hours of treatment. The chance of cure after day seven of treatment was higher in the racecadotril group when compared to the control group. Racecadotril with ORS was comparable to ORS alone in terms of safety and tolerability. Conclusion: There is evidence that the drug racecadotril holds promise in terms of reducing stool output, number of bowel movements and duration of diarrhea. However, well-designed randomized control trails with an ad equate sample size and absence of any competitive interest in studying the efficacy and safety of racecadotril in acute diarrhea are needed before we reach any conclusion regarding the role of the drug in diarrhea.

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Pediatric acute gastroenteritis remains an Description of Intervention important clinical illness commonly Racecadotril represents a promising new encountered by physicians. Its attendant approach to the treatment of diarrhea. It is a problems of vomiting, diarrhea and lipophilic diesterified pro-drug of the dehydration continue to pose significant risks enkephalinase inhibitor thiorphan. Racecadotril to children and are responsible for considerable is rapidly converted to thiorphan, which then health care expenditures. Estimates of the interacts specifically with the active site of overall incidence of acute gastroenteritis range enkephalinase to produce potent blockade of from 1.3 to 2.3 episodes of diarrhea per year in the enzyme, thus, preventing inactivation of children under five years of age. Each year, endogenous opioid peptides (enkephalins) more than 300 U.S. children die from this released by submucosal and myenteric illness. 1 In the United States alone, neurons. Inhibition of enkephalinase by gastroenteritis accounts for more than 220,000 thiorphan increases the availability of opioids, hospital admissions per year in children less which activate delta (δ) opioid receptors in the than five years of age, or approximately 10 gastrointestinal tract. 5 This in turn leads to a percent of hospitalizations in this age group. 1 In reduction in cAMP mucosal levels, resulting in a the local setting, the Department of Health reduction in the secretion of water and reported that for the past 20 years, diseases electrolytes into the intestinal lumen. related to diarrhea has been the number one Data from studies carried out in both adults cause of morbidity and mortality. The incidence and children in Europe have provided evidence rate is as high as 1,997 per 100,000 population of the effectiveness of racecadotril in reducing while the mortality rate is 6.7 percent per stool output and duration of diarrhea. In the 100,000 population. 2 guidelines published in the May 2008 issue of Through the years, acute gastroenteritis has the Journal of Pediatric Gastroenterology and been the subject of considerable and Nutrition, one of the most innovative concepts worldwide attention and effort. Particular included in these guidelines is the attention emphasis has been given to the development given to racecadotril or acetorphan. However, and promotion of inexpensive, easy-to-use oral it was pointed out that there is a need for more rehydration solutions (ORS) for the treatment trials, especially in the larger outpatient of diarrhea; it is designed to replace and setting. 6 maintain fluid levels combined with For this reason, a systematic review of appropriate nutrition. However, despite the clinical trials is needed to determine the overall fact that the American Academy of Pediatrics effect of racecadotril as an adjuvant therapy in and Centers for Disease Control and Prevention the treatment of diarrhea among children. have published practice parameters for management of acute gastroenteritis, studies OBJECTIVES have shown ORS continues to be underused The main aim of the study is to assess the globally. 3 The main reason for such is that it effectiveness and safety of racecadotril does not reduce the frequency of bowel supplementation, along with oral rehydration movement and fluid loss nor shorten the solution, in the treatment of diarrhea in duration of diarrhea. 4 Hence, several children. measures have been investigated as adjunct This research specifically seeks to determine therapy including a variety of non specific anti- the efficacy and safety of racecadotril plus oral diarrheal agents, anti-motility agents and anti- rehydration versus oral rehydration alone as secretory agents such as racecadotril or well as determine the effect of racecadotril in acetorphan. reduction of stool output and the duration of diarrhea, the number of follow up visits to the

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21 PIDSP Journal 2010 Vol 11 No.2 Copyright ® 2010 emergency room or primary doctor, and the experts in the field were asked to identify safety and tolerance of the drug in children . unreported trials.

MATERIALS AND METHODS Data collection and analysis Criteria for considering studies for this review Data extraction and management Types of studies Three reviewers independently assessed The trials were randomized, placebo- the methodological quality of the studies controlled in a hospital setting or out-patient according to criteria used by the Cochrane department. Infectious Disease Group. Each of the co- Types of Participants authors independently assessed the suitability Participants of this study include pediatric of each study for inclusion in the meta-analysis; patients of any age who were identified to have the results of these individual assessments acute gastroenteritis or diarrhea and were seen were then compared. In cases in which the in the hospital setting or as out patients. original opinions varied, these differences were Diarrhea was defined as three or more loose resolved through consensus by using the pre- stools in 24 hours regardless of etiology. established inclusion criteria or further written Types of Intervention elaborations of said criteria, when necessary. Patients for the experimental group Studies were assessed as high-quality if they received racecadotril at a dosage regimen of fulfilled the following criteria: (1) treatment 1.5 mg/kg every eight hours as an adjunct to allocation was randomized with adequate ORS. Patients in the control group received concealment; (2) the treatment and control placebo treatment and ORS. groups were balanced in terms of known Types of outcome measures determinants of outcome; (3) outcome Primary outcome measured were stool assessment was done in a double-blind output in 48 hours and for the duration of manner; (4) outcome detection methods used diarrhea. Secondary outcome measures were similar for both groups; (5) treatment and included: (1) number of follow up visits to control groups were treated equally in terms of pediatricians or emergency department after other therapeutic and co-interventions 48 hours of treatment; (2) cure rates defined as received, frequency of follow-up and general percentage of children who no longer exhibit quality of care; (6) an intention-to-treat analysis more than three bowel movements in a day or was conducted; and (7) drop-out rates between with at least one formed stool in 24 hours; and groups were comparable. On the other hand, (3) adverse effects. studies were considered fair-quality if any subtle biases were present, such as: (1) unclear Search methods for identification of studies allocation concealment; (2) absence of blinding; A highly sensitive search strategy was used and (3) no intent-to-treat analysis. And lastly, for identifying randomized controlled trials. studies were considered low-quality if any of Both electronic and manual means of retrieving the frank biases was seen: (1) significant relevant studies were performed. PUBMED and differences between the treatment and control COCHRANE Library were searched irrespective group in terms of known predictors of of language and publication status. The search outcome; (2) obvious differences in the general strategy combined the search terms quality of care received by subjects in both “randomized controlled trials”, “racecadotril” groups; (3) marked difference in drop-out rates; and “diarrhea”. The reference lists of all and (4) outcome detection methods were identified papers were searched for further different for both groups. information. Authors for unpublished studies were also contacted. Colleagues and other

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Measures of treatment effect RESULTS All the outcome measures were combined Description of studies and analyzed using a fixed-effect model in After searching PUBMED and the Cochrane Review Manager (RevMan) Version 5. The Central Register of Controlled Trials (CENTRAL), outcomes were classified as dichotomous or a total of 13 studies were identified to be continuous, based on the definition by the potentially eligible for inclusion in the meta- Cochrane Handbook of Systematic Reviews. The analysis. After thorough scrutiny, nine articles comparison was classified as dichotomous if were excluded due to specific reasons (Figure the outcome is one of only two possible 1). Four studies were left for more detailed categorical responses. For dichotomous data, review; however, there was a trial that was the risk ratio or the probability that an event excluded because it compared racecadotril with will occur was determined for each loperamide. Reference lists of articles were comparison. The number of children who reviewed and two more trials were identified. visited the emergency department, the number One trial fulfilled the selection criteria and was of children who were cured after seven days included in this review. The other study was were all considered dichotomous in this study. excluded since it was not a randomized Continuous data are those that can take any controlled trial. Four articles remained and value in a specified range. The standardized these were used in this review mean difference (SMD) was used to combine Four randomized controlled trials involving 659 results from studies using different ways of participants (racecadotril = 332; control = 327) measuring the same concept. The stool output, met our inclusion criteria. 7-10 Two of these the number of bowel movements in 48 hours, studies were placebo-controlled (Salazar –Lindo and the duration of diarrhea were all 2000, Cezard 2001), Error! Bookmark not considered continuous data in this review. defined. -Error! Bookmark not defined. and in Dealing with missing data the other two trials (Cojucaru 2002, Santos Missing statistics like standard deviation 2009), treatment was compared with no was obtained using the actual p values given in intervention. Majority of the trials were the studies. The Standard deviation was conducted in Europe: two trials were extracted by obtaining the corresponding t performed in France, (Cojucaru 2002, Cezard value from the table of the t distribution and 2001), Error! Bookmark not defined. ,Error! transforming the t value into the standard Bookmark not defined. while the other one deviation [SD = (mean change/ t value) / square was in Spain (Santos 2009). Error! Bookmark root of (1/n 1 + 1/n 2)]. not defined. A lone study was conducted in a Assessment of heterogeneity third world country (Salazar-Lindo 2001). Error! Heterogeneity was quantified using the chi Bookmark not defined. These studies used square test for heterogeneity with p <0.10 as racecadotril plus ORS, as compared to receiving the cut-off for significant heterogeneity. standard rehydration solution alone as Heterogeneity can be interpreted as a treatment for children with acute percentage of total variation between studies gastroenteritis. that is attributable to heterogeneity rather Participants of the studies were children aged than to chance. I 2 test was used to assess the three-to-48 months. Two studies were degree of heterogeneity, i.e. I 2 > 50% suggests exclusively conducted among patients who significant degree of heterogeneity or a value were hospitalized (Salazar –Lindo 2000, Cezard of 0% indicates no observed heterogeneity . 2001?), Error! Bookmark not defined. ,Error! Bookmark not defined. while the other two were done in an out-patient setting (Cojucaru 2002 , Santos 2009). 9,10 Although in all of the

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23 PIDSP Journal 2010 Vol 11 No.2 Copyright ® 2010 studies conducted the participants recruited from one study were those who had chronic had acute gastroenteritis, there were variations diarrhea or had weight for age deficit of in the criteria for diarrhea and its duration 20% or with before they were enrolled. Excluded subjects Figure 1. Flow Diagram of Included Studies

Potentially relevant studies identified: citations or abstracts screened for retrieval (n=13)

OUT Studies excluded: • Different study population ( adults, HIV patients, animals ) ( n= 9)

Studies retrieved for more

detailed evaluation (n=4)

OUT Studies excluded:

• Compared racecadotril with loperamide (n=1)

IN

Studies identified and reviewed using reference

lists (n=2)

Potentially appropriate studies to be included in meta-analysis (n= 5)

OUT

Not randomized controlled trial (n=1)

Randomized controlled trials on racecadotril compared to ORS in children Downloadedwith from diarrhea www.pidsphil.org (n=4)

24 PIDSP Journal 2010 Vol 11 No.2 Copyright ® 2010

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25 PIDSP Journal 2010 Vol 11 No.2 Copyright ® 2010 systemic illness or those who received anti- criteria but are well known and are likely to be diarrheals or antibiotics (Cezard 2001). thought of by readers. One study (Santos 2009) mentioned Risk of bias in included studies specifically that it excluded subjects who had All of the trials included in this study were previous exposure to antidiarrheals or randomized at level of treatment. However, not antibiotics. Subjects were likewise excluded if all studies described their method of allocation they had more than seven days of symptoms generation concealment. These studies were and allergy to any component of the drug. Boys assessed to have an unclear risk for bias with blood and stool, severe dehydration, or (Salazar-Lindo 2000, Cezard 2001, Cojucaru any concomitant serious illness were excluded 2002,). In all four trials, only two (Salazar-Lindo in the study conducted by Salazar-Lindo, et al. 2000, Cezard 2001) met the criteria for The etiology of diarrhea was mentioned in blinding, which suggests low risk for bias for the three trials naming rotavirus as the former and high risk of bias for the other two predominant agent (Salazar-Lindo 2000, Cezard trials( Cojucaru 2002, Santos 2009). In the 2001, Santos 2009). None of the studies criteria for selective outcome reporting and provided data for the hydration status of the frank bias, all were met; hence, a low risk of subjects. All four studies provided information bias for these key domains. Incomplete about adverse events which included mild outcome of data were addressed by two trials hypokalemia, ileus, mild fever, respiratory (Cezard 2001, Santos 2009), one study illness (rhinitis, bronchitis, coughing, (Cojucaru 2002) had a potential high risk of pneumonia, upper respiratory infection) and bias, while the other study remained uncertain exanthem. Outcome measured was stool ( Salazar-Lindo 2000). output using g/kg or g/hr, however only two Effects of interventions studies provided data on stool output during Stool output in 48 hours the first 48 hours ( Salazar–Lindo 2000, Cezard Two studies assessed the effect of 2001).7,8 Furthermore, two studies reported racecadotril on stool output in 48 hours stool output in terms of presence of positive (Salazar-Lindo 2000, Cezard 2001). Standard culture on rotavirus (Salazar –Lindo 2000, mean difference (SMD) was taken for the two Cezard 2001). All RCT’s provided information trials comparing racecadotril with placebo in on the duration of diarrhea, although, reporting decreasing the stool output from baseline to of outcomes varied in terms of measurement. that after the treatment with racecadotril. Number of follow up visits were reported in Figure 4.1 shows the comparison of the two two studies (Cojucaru 2002, Santos 2009) 9,10 groups regardless of the etiology of the while cure rates data were given in three trials gastroenteritis. A significant difference favoring (Salazar –Lindo 2000, Cojucaru 2002, Santos the use of racecadotril in decreasing the stool 2009). 7,8,10 output was noted (p= 0.000001). Test for heterogeneity was not statistically significant Excluded Studies (p=0.86). The brief list of excluded studies is Stool volume in rotavirus positive patients presented in the references. It does not contain When patients were further analyzed in all articles identified by the comprehensive terms of rotavirus status, the two studies search as suggested by the Cochrane Handbook (Salazar-Lindo 2000, Cezard 2001) version 5. It only covers all studies that may on demonstrated once more a significant the surface appear to have met the eligibility difference between racecadotril and placebo criteria, but on further inspection, do not. Also treatments favoring the experimental group. included are studies that do not meet the SMD for stool output was -0.99 (95% CI -1.36 to -0.62, Z=5.22, p < 0.00001) [Figure 4.2]. The

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26 PIDSP Journal 2010 Vol 11 No.2 Copyright ® 2010

Table 1. Included Studies in the Meta Analysis AUTHOR SUBJECT AGE INCLUSION/ Etiology TREATMENT REGIMEN Duration of OUTCOME (N) treatment Santos 189 3-48 3 looses stools Viruses N= 88 Until 2 stools of Stool volume in rotavirus (Spain) children months within 24 hrs (50.5%) 10 mg every 8 hr if less normal positive patients Out patient Rotavirus than 9kg; 20 mg every 8 consistency, no Number of bowel 23.6% hrs if weight bet 9-13 bowel movement movements after 48 hrs, kg; 30 mg every 8 hrs if in 12 hrs, number of children who Bacteria more than 13 kg maximum of 7 followed up (8.7%) days duration of diarrhea in days 135 3-48 Acute watery Bacteria N= 68 5 days or unti l Stool output in 48 hrs in Salazar –Lindo children months diarrhea( 3 or more (34%) Racecadotril 1.5 mg/kg cessation of g/kg (Peru) mean age: stools in 24 hrs Rotavirus every 8 hr diarrhea intake of ORS, 13 months; before admission, (54%) stool output in rotavirus hospitalized at least 1 stool positive boys within 4-6 hrs after admission Cezard 168 Mean age : Acute watery N=89 racecadotril 5 days or until Stool output in g/hr, stool (France) children 12.8 diarrhea 3 watery Rotavirus(40 1.5 mg/kg every 8hr cessation of output in rotavirus positive months stools per day at %) diarrhea in 48 hrs (range 3.5- least 72 hrs Adenovirus(4 6.8 mo) %) Salmonella(4 hospitalized %) E.coli(3%) Negative culture (36%) Cojucaru 164 3-48 Acute diarrhea No data N=81 racecadotril ( 3 - Until cessation of Number of bowel (France) children months, more that 3 stools 10mg/day if less than 9 diarrhea ( no loose movements in 48 hr, outpatient per day kg; 3-20 mg/day if more stools for 12 hrs, duration of diarrhea in than 9 kg maximum of 7 hours, days number of children who followed up

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some missing data so pooling of all studies was Figure 2. Methodological quality summary not possible. In the study by Salazar-Lindo, et al, duration of diarrhea differed depending on whether it was caused by rotavirus or not. As compared to placebo, the duration of diarrhea for patients who were negative for rotavirus was 28 hours vs. 52 hours; while the duration for those who were positive for rotavirus was 28 Allocation concealment? Allocation generation sequence adequate blinding bias other of free reporting? selective of free data addressed? outcome incomplete hours vs. 72 hours. Cezard on the other hand Cezard 2001 ? ? + + + + reported reduced time to recovery (8 hours) for Cojocaru 2002 – ? – + + – rotavirus positive patients in the racecadotril Salazar -LIndo ? ? + + + ? group versus the control (26 hours). Cojucaru, Santos 2009 ? + ? + + + et al, reported that duration of diarrhea was shorter for the experimental group versus the Legend (+) yes, (-) no, (?) unclear control (97 ±35.6 hr vs. 137±42.4). Lastly, trials were shown to be homogenous (p = 0.18, Santos calculated an average of four days (± 2.1 I2 = 44%). SD) of diarrhea in the racecadotril group and Number of Bowel Movements in 48 hours 4.7 days (± 2.2 SD) in the hydration group. Two studies assessed the effects of Number of children who visited the ER or their racecadotril on the number of bowel pediatricians after 48 hours of treatment movements in 48 hours (Cojucaru 2002, Santos The number of children who visited their 2009). SMD for the two trials comparing pediatricians or the emergency department racecadotril to placebo in reducing bowel after treatment was reported in two studies movements from baseline to that after (Cojucaru 2001, Santos 2009). There was a treatment was -0.36 (95% CI -0.57 to -0.14 , statistical difference noted favoring those who Z=3.30, p < 0.0010). However test for were given racecadotril. (RR=0.62, 95% CI 0.40 heterogeneity was statistically significant to 0.97, Z=2.10 p=0.04). Homogeneity was (p=01, I 2 = 83%). found in the two studies as well. (p=0.41 I 2 Duration of diarrhea =0%). In the trials conducted by Cojucaru and Cure rates in 7 days Santos, there was a significant difference Three studies assessed recovery of children between patients who received racecadotril in after treatment (Salazar-Lindo 2000, Cezard terms of the duration of diarrhea with an SMD 2001, Santos 2009). Pooled relative risk of of -0.63 (95% CI -0.85 to -0.41, Z=5.73, children who recovered after treatment from p<0.00001) [Figure 4.4]. However, the studies three trials was 0.70 (95%CI 0 .49 to 0.99). A were significantly heterogeneous (p = 0.002, I 2 significant difference favoring the use of =90%). racecadotril was noted ( p= 0.05). Test for All randomized controlled trials provided heterogeneity was not statistically significant data on duration of diarrhea; however, the (p=0.17 I 2 =43%) (Figure 4. 5). reporting of outcomes was inconsistent with

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Figure 4.1. Stool volume in 48 hours measured in g/hr or g/kg Experimental Control Std. Mean Difference Std. Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI Cezard 2001 9 9.2 84 15 9.1 82 55.3% -0.65 [-0.97, -0.34] Salazar -LIndo 2000 92 99 68 170 122.8 67 44.7% -0.70 [-1.04, -0.35]

Total (95% CI) 152 149 100.0% -0.67 [-0.90, -0.44] Heterogeneity: Chi² = 0.03, df = 1 (P = 0.86); I² = 0% -100 -50 0 50 100 Test for overall effect: Z = 5.67 (P < 0.00001) Favours experimental Favours control

Figure 4.2. Stool volume in g/hr or g/kg in rotavirus- positive patients Favours experimental Control Std. Mean Difference Std. Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI Cezard 2001 8.5 7.3 24 19 8.4 31 39.7% -1.30 [-1.89, -0.71] Salazar -LIndo 2000 105 99 34 195 124.9 39 60.3% -0.78 [-1.26, -0.31]

Total (95% CI) 58 70 100.0% -0.99 [-1.36, -0.62] Heterogeneity: Chi² = 1.80, df = 1 (P = 0.18); I² = 44% -100 -50 0 50 100 Test for overall effect: Z = 5.22 (P < 0.00001) Favours experimental Favours control

Figure 4.3. Number of bowel movements after 48 hours Experimental Control Std. Mean Difference Std. Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI Cojocaru 2002 6.8 3.8 81 9.5 4.5 83 45.3% -0.64 [-0.96, -0.33] Santos 2009 3.8 2.4 94 4.1 2.7 94 54.7% -0.12 [-0.40, 0.17]

Total (95% CI) 175 177 100.0% -0.36 [-0.57, -0.14] Heterogeneity: Chi² = 5.92, df = 1 (P = 0.01); I² = 83% -100 -50 0 50 100 Test for overall effect: Z = 3.30 (P = 0.0010) Favours experimental Favours control

Figure 4.4. Duration of diarrhea in days Experimental Control Std. Mean Difference Std. Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI Cojocaru 2002 4.05 1.48 81 5.73 1.77 83 43.8% -1.02 [-1.35, -0.70] Santos 2009 4 2.1 94 4.7 2.2 94 56.2% -0.32 [-0.61, -0.04]

Total (95% CI) 175 177 100.0% -0.63 [-0.85, -0.41] Heterogeneity: Chi² = 9.94, df = 1 (P = 0.002); I² = 90% -100 -50 0 50 100 Test for overall effect: Z = 5.73 (P < 0.00001) Favours experimental Favours control

Figure 4.5. Number of children who followed up after treatment Experimental Control Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Cojocaru 2002 5 81 8 83 22.9% 0.64 [0.22, 1.88] Santos 2009 14 76 27 78 77.1% 0.53 [0.30, 0.93]

Total (95% CI) 157 161 100.0% 0.56 [0.34, 0.92] Total events 19 35 Heterogeneity: Chi² = 0.09, df = 1 (P = 0.76); I² = 0% 0.01 0.1 1 10 100 Test for overall effect: Z = 2.30 (P = 0.02) Favours experimental Favours control

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Figure 4.6. Cure rates of children in 7 days Experimental Control Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Cezard 2001 11 89 14 83 24.2% 0.73 [0.35, 1.52] Salazar -LIndo 2000 11 68 23 67 38.6% 0.47 [0.25, 0.89] Santos 2009 15 50 23 53 37.2% 0.69 [0.41, 1.17]

Total (95% CI) 207 203 100.0% 0.62 [0.43, 0.88] Total events 37 60 Heterogeneity: Chi² = 1.09, df = 2 (P = 0.58); I² = 0% 0.01 0.1 1 10 100 Test for overall effect: Z = 2.68 (P = 0.007) Favours experimental Favours control

Figure 4.7. Adverse events Experimental Control Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Cezard 2001 9 89 9 83 21.1% 0.93 [0.39, 2.24] Cojocaru 2002 10 81 11 83 24.6% 0.93 [0.42, 2.07] Salazar -LIndo 7 68 5 67 11.4% 1.38 [0.46, 4.13] Santos 2009 18 94 19 94 43.0% 0.95 [0.53, 1.69]

Total (95% CI) 332 327 100.0% 0.99 [0.67, 1.46] Total events 44 44 Heterogeneity: Chi² = 0.41, df = 3 (P = 0.94); I² = 0% 0.01 0.1 1 10 100 Test for overall effect: Z = 0.05 (P = 0.96) Favours experimental Favours control

Adverse events chance for cure in seven days was also All four studies provided information about significantly higher in the racecadotril group. adverse events. None demonstrated a The safety and tolerability was comparable to significant difference in the frequency of the control group. adverse events between the experimental Overall completeness and applicability of group and control group. Reported adverse evidence events for all trials were vomiting, mild fever, The findings on stool output, number of ileus, mild hypokalemia, poor taste, exanthem bowel movements and duration of diarrhea are and respiratory problems (Figure 4.6). worth reporting because quantitative diarrhea criteria are recommended by the World Health DISCUSSION Organization for the evaluation of therapeutic Summary of main results agents in the management of acute diarrhea. 11 The meta-analysis of pooled data from 4 Unfortunately, the measure on the duration RCTs (racecadotril = 332, control = 327) showed of diarrhea is not considered optimal in our that in children with acute gastroenteritis, meta-analysis. Because the units of reporting whether caused by rotavirus or not, the duration of diarrhea were inconsistent racecadotril significantly reduced stool output among the studies, there was a need for us to in 48 hours and decreased the duration of standardize the results to a uniform scale diarrhea as compared with ORS alone. These before eventually combining them were the primary outcomes measured in the (standardized mean difference method). This studies. For the secondary outcomes makes the overall treatment effect difficult to measured, racecadotril likewise was interpret as it is in units of standard deviations significantly better than the control group in rather than in any of the units used in the reducing the number of children who revisited individual trials. It is also unclear as to what their doctors after 48 hours of treatment. The constitutes a clinically important change. 12, 13

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For these reasons, homogenous data were not positive with rotavirus and received present as well. racecadotril . In actuality, there are various Another important outcome measured was agents that can cause acute gastroenteritis. the effect of racecadotril on stool output. Perhaps a better analysis can be done on Although all four trials suggest benefit of specific agents alone or pooling of data on all racecadotril therapy as an adjunct in reduction trials, irrespective of etiology. of stool output or number of bowel Racecadotril was better in terms of cure movements, the authors point out several rate and number of follow up consultations factors that should be taken into consideration. after treatment. It should be pointed yet again, First, two studies included were in hospital- though, that the settings were different for the based settings while the other two were in out- various trials. Studies done in the outpatient patient settings: this makes it difficult to settings lacked monitoring of the generalize the results. This difference may be administration or response to treatment, related to severity of diarrhea; those admitted hence, no direct observation was made which to the hospital may have been more severely could provide bias to our analysis. dehydrated and thus more responsive to In general, racecadotril has been reported treatment. Evaluation within these subgroups is to have a good safety profile; this was then warranted. Perhaps more studies from confirmed by our review which showed that the outpatient department are needed since the side effects were similar with placebo and treatments there are more standardized. no serious events related to study treatment Second, most of the studies showed rotavirus was observed in all trials. This finding then as the predominant etiologic agent for the confirms that racecadotril is a safe drug for gastroenteritis. Our analysis showed that children. Even in adults, majority of authors racecadotril was particularly efficient in agree that the drug is indeed well tolerated. 15, rotavirus-positive children. This may be due to 16 two events: the higher stool output in Quality of evidence and the potential biases in rotavirus-positive patients and pharmacological the review process properties of racecadotril. Rotavirus increases Meta-analysis techniques are increasingly the severity of diarrhea, especially with regard being used to consolidate results from multiple to stool output. The increased efficacy of studies of the same topic and to develop racecadotril in rotavirus patients could be evidence-based policies for clinical practice and related to the fact that a pharmacological effect public health programming. The reliability of is more likely shown when symptoms are more the conclusions derived from meta-analyses pronounced. Rotavirus induces a secretory depend on the methodological quality of the process at the enterocyte level that could be original studies, the appropriateness of the counteracted by racecadotril. After all, study, inclusion criteria, and the thoroughness racecadotril is a synthetic enkephalinase of the review and synthesis of inhibitor and its anti-diarrheal effects are information. Error! Bookmark not defined. attributed to its anti-secretory properties Given the fact that none of the four trials mediated by inactivating endogenous opioid included in our analysis seemed peptides, enkephalins, secreted by myenteric methodologically sound, this posed a potential and submucus plexus in the digestive tract. problem. For one, all trials had unclear or Additionally, racecadotril works best when inadequate allocation concealment which may hypersecretion is present. 14 This pharmacologic result in overestimation. Secondly, two trials property of racecadotril may also be the reason were not blinded, which can be a source of why there was also a significant decrease in potential bias. Thirdly, we cannot fully exclude stool volume among patients who tested publication bias. According to Bhan, et al, there

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31 PIDSP Journal 2010 Vol 11 No.2 Copyright ® 2010 was a drug company that did a multi-center important to note that racecadotril was trial on racecadotril which was not published. 17 compared with loperamide. 20 This raises the issue that the scientific evidence shown to physicians is not the total evidence CONCLUSIONS/RECOMMENDATIONS obtained through clinical trials and may Implications for practice and research represent selective presentation of trials. While There seems to be evidence that the drug we recognize the hesitation of journals to racecadotril holds promise in terms of publish negative trials it is nevertheless an issue improving diarrhea quantitatively. However, of concern. Another source of bias is that two well-designed RCT’s, ad equate sample size and trials were funded by a drug company; given absence of any competitive interest in studying these considerations, some caution must be the efficacy and safety of racecadotril in acute exercised in interpreting strength of evidence. diarrhea, are needed before we reach a more Lastly, a lthough the included studies were not valid and generalized conclusion regarding the significantly heterogeneous, given the small role of the drug in the management of acute number of studies, statistical conclusions on diarrhea . determinants of heterogeneity might be still be References to studies flawed. Included Studies 1. Santos M, Marañón R, Miguez C, Vázquez P, Agreements and disagreements with other Sánchez C. Use of racecadotril as outpatient studies of reviews treatment for acute gastroenteritis: a The result of this review is in agreement prospective, randomized, parallel study. J with a systematic review done by Szajeweska Pediatr. 2009 Jul;155(1):62-7. who concluded that in three relatively small 2. Cojucaru B, Bocquet N, Timsit S, Wille C, RCT’s with some methodological problems, Boursiquot C, Marcombes F, Garel D, Sannier N, racecadotril was effective in reducing the Chéron G. [Effect of racecadotril in the volume of stool output and in reducing management of acute diarrhea in infants and duration of diarrhea. An RCT done in 110 adults children] Arch Pediatr. 2002 Aug; 9(8):774-9. with severe cholera reported comparable total French . stool output, total ORS intake or duration of 3. Cézard JP, Duhamel JF, Meyer M, Pharaon I, diarrhea between the racecadotril and Bellaiche M, Maurage C, Ginies JL, Vaillant JM, 18 loperamide groups. A recent RCT comparing Girardet JP, Lamireau T, Poujol A, Morali A, racecadotril and loperamide for stopping acute Sarles J, Olives JP, Whately-Smith C, Audrain S, diarrhea in adults found comparable clinical Lecomte JM. Efficacy and tolerability of racecadotril in acute diarrhea in children success rates and mean duration of diarrhea. Gastroenterology. 2001 Mar;120(4):799-805 More patients on loperamide had reactive constipation; itching was notably higher in the 4. Salazar-Lindo E, Santisteban-Ponce J, Chea-Woo racecadotril group. 19 Both studies mentioned E, Gutierrez M. Racecadotril in the treatment though compared racecadotril with loperamide of acute watery diarrhea in children. N Engl J Med. 2000 Aug 17; 343(7):463-7. and were carried out in adults. Turk, et al. on the other hand, did a multicentre, parallel- Excluded studies group, double-blind, placebo-controlled study Alam NH, Ashraf H, Khan WA, Karim MM, Fuchs GJ Efficacy and comparing racecadotril with loperamide which tolerability of racecadotril in the treatment of cholera in adults: a double blind, randomised, controlled clinical trial. Gut. 2003 found no significant differences in fecal output Oct; 52(10):1419-23\ nor duration of diarrhea. However, there were Bergmann JF, Chaussade S, Couturier D, Baumer P, Schwartz JC, differences in tolerance, with a lower incidence Lecomte JM. Effects of acetorphan, an enkephalinase inhibitor, on experimental and acute diarrhoea. Aliment Pharmacol Ther. of constipation and fewer associated treatment 1992 Jun; 6(3):305-13. modifications in the racecadotril group. It is Beaugerie L, Baumer P, Chaussade S, Berard H, Rozenbaum W, Pialoux G, Le Quintrec Y, Schwartz JC, Lecomte JM. Treatment of refractory diarrhoea in AIDS with acetorphan and octreotide:

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