Methods
This is an updated systematic review of the published review “Prokinetics For The Treatment of Functional Dyspepsia: Bayesian Network Meta-analysis” [
2]. An updated search was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) extension statement [
5,
6]. (Supplementary file
3, PRISMA NMA checklist)
Literature search
An updated search in Pubmed, EMBASE, Cochrane Library, and Web of Science was conducted in literatures published from July 2015 to March 2023 without limitations on language or document type. Search strategies used in all databases are described in detail (Supplementary file
1, Search strategy). Reference lists of the included studies and relevant systematic reviews were reviewed to identify any additional papers. Clinicaltrials.gov and WHO trials registry were also searched for registered trials. We also contacted experts in this field to identify additional studies.
Study selection
Two reviewers independently screened studies by viewing titles and abstracts. All potentially relevant citations were requested and inspected in detail using the full-text version. Disagreements were resolved by discussion with assistance from a third party, if necessary. A PRISMA flow diagram was constructed to show the full study-selection process.
Studies were selected if they met inclusion criteria: (1) Adult patients (at least 18 years old) diagnosed with symptoms of FD as defined by the original studies, (2) Randomized controlled trials (RCTs), (3) Treatment regimens that included drugs listed below: 1) Metoclopramide (Maxolon, Rimetin, Primperan, Reglan, Cerucal, clopamon, clopram, degan, emperal, imperan, metamide, metagliz, metozolv, pulin and terperan), 2) Mosapride, 3) Domperidone (Domperidon, Domidon, Gastrocure, Motilium), 4) Itopride (itopride, ganaton), 5) Acotiamide, 6) Cinitapride (Cidine, cinitaprid, Blaston), 7) Placebo. We only included single use of the above-listed drugs. There were no limitations on dosage, frequency time, treatment duration, and method of administration.
Exclusion criteria were: (1) other diseases of the upper gastrointestinal tract and upper abdominal organs that may present with similar dyspeptic symptoms (gastrointestinal malignancy, peptic ulcer, liver, gallbladder, and pancreatic disease), (2) studies that did not report eligible outcome data and studies that did not provide access to a full report. Moreover, we excluded trimebutine as it is not classified as a prokinetic drug.
For each study, the following information was extracted by two independent reviewers: first author’s name, year of publication, country, diagnosis, sample sizes at random, sex and age of patients, intervention, drugs, dosage, effect size of the intervention and control groups, data and definition of outcome, and measurement time. Disagreements were resolved by discussion with assistance from a third party, if necessary. If multiple publications were reported for the same study, we extracted all data from the companion studies and removed the duplicated data.
Quality assessment / risk of bias analysis
Two reviewers independently assessed the risk of bias of the included studies. We assessed each domain for risk of bias according to the standard criteria outlined in the Cochrane Handbook [
7], including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other bias. Disagreements were resolved by discussion with assistance from a third party, if necessary.
Outcome assessment
The primary outcome was the therapeutic efficacy (total efficacy rate). The secondary outcome was adverse events, including total adverse events, drug-related adverse events, and specific adverse events.
Statistical analysis
As the efficacy is a representative of dichotomous outcomes, odds ratios (ORs) and 95% confidence intervals (CIs) were used as outcome measures. It could be simply explained that the experimental group exhibited a significantly higher efficacy compared to the control group when the ORs and its 95% CIs are more than 1. Where possible, we used the ORs based on an intention-to-treat (ITT) analysis of the population. A Bayesian network meta-analysis was performed using the network package (gemtc package) in R Studio 4.0 software. The fixed-effect models were used. The pooled estimation and the probability of identifying the most efficacious drug were obtained using the Markov Chains Monte Carlo method [
8]. Evidence inconsistency and clinical similarity in patient characteristics and settings across trials were carefully assessed. Network geometry was performed using R software. Network geometry used nodes to represent different interventions and edges to represent the head-to-head comparisons between interventions. The size of nodes and thickness of edges were associated with the number of patients receiving specific interventions and the number of included trials, respectively. The node split method was used to check for consistency in the network. Based on these results, we calculated the surface under the cumulative ranking curve (SUCRA), which is the converted value reflecting the probability of a treatment being the best according to the ranking of each treatment [
9]. A higher SUCRA value indicates better therapeutic results based on the indirect comparison method [
10].
Discussion
This updated network meta-analysis included an additional four RCTs [
3,
4,
11,
12] in comparison to the previously published meta-analysis [
2]. The findings from this network meta-analysis indicated that the total efficacy rates of six prokinetic agents—metoclopramide, cinitapride, mosapride, domperidone, itopride, and acotiamide—were superior to that of the placebo. While there was no statistically significant difference in the total efficacy rate between metoclopramide and cinitapride, metoclopramide exhibited a significantly higher efficacy compared to the other four prokinetic treatments. Furthermore, cinitapride demonstrated a higher total efficacy rate than mosapride.
In our study we also calculated the SUCRA, which could reflect the probability of a treatment being the best according to the ranking of each treatment [
9]. A higher SUCRA value indicates a higher probability of better treatment effect [
10]. The ranking probability analysis indicated metoclopramide as the top-ranking treatment, followed by cinitapride, then domperidone, acotiamide, itopride, mosapride and placebo. When using SUCRA to evaluate the total adverse events and drug-related adverse events related to prokinetics, higher value means higher probability of a safer drug. However, the stability of these rankings should be interpreted cautiously, as they can be influenced by factors such as the number of included studies, the number of events, and the overall sample size.
The precise underlying pathogenesis of FD remains uncertain. Many contributing factors, including gastroduodenal motility abnormalities, visceral hypersensitivity, gastric acid,
Helicobacter pylori infection, and psychosomatic influences, are believed to be implicated in the pathogenic process. Numerous clinical studies and meta-analyses have explored the effectiveness of therapies targeting the inhibition of visceral hypersensitivity, acid suppression,
Helicobacter pylori eradication, and antipsychotic interventions for FD treatment. These studies have also conducted comparisons of the efficacy and adverse event profiles of various drugs [
36‐
40]. Both the prior meta-analysis [
2] and our current updated network meta-analysis have evaluated the therapeutic effects of distinct prokinetic agents for the treatment of FD. The objective of both of these meta-analyses is to offer clinicians additional evidence to aid in their selection of appropriate prokinetic agents. Our results confirmed that the six prokinetic agents included in the analysis were all significantly better than placebo. This revealed that prokinetic drugs should be effective in the treatment of FD. The treatment ranking probability showed that metoclopramide and cinitapride ranked the top two most effective drugs, suggesting that these two prokinetic agents may be the preferred drugs in FD treatment.
Prokinetic drug is a group of important therapy to improve the symptoms of FD, especially for FD patients with PDS. At present, various prokinetic agents have been used to treat FD. Cinitapride is a prokinetic agent that has dual effects of 5-HT receptor agonist and dopamine receptor antagonist. It has been proved that cinitapride can promote gastric emptying and motility, therefore, can be used in the treatment of motility related diseases such as dyspepsia, gastroesophageal reflux disease and so on [
3]. Although clinical trials have been verified the effectiveness of cinitapride for FD [
3,
14], the treatment status of cinitapride for FD compared with other prokinetic drugs remains unclear. Young Joo Yang conducted a meta-analysis comparing prokinetic agents for FD in 2017 and found that the treatment effect of metoclopramide, mosapride and domperidone is superior to itopride or acotiamide [
2]. However, cinitapride was not included in the meta-analysis. In our update study, RCTs evidence relevant to cinitapride were included and a network meta-analysis was conducted. Results showed that cinitapride and metoclopramide were better than other prokinetic drugs for the treatment of FD. Our results are consistent with the results of a recently published meta-analysis conducted by Liang Liang and colleagues [
41]. The authors compared the effects of different categories of drugs with different mechanisms for FD. The results showed that the antidepressant levosulpiride ranked the highest, followed by cinitapride ranked second among all drugs. Meanwhile, cinitabride was superior to other prokinetic and anti-acid agents [
41].
However, the adverse events associated with the interventions have to be considered when selecting prokinetics. Result showed that cinitapride had lower risk of total adverse events than domperidone; however, there was no difference for total adverse events between acotiamide, mosapride and placebo. There was also no difference in drug-related adverse events between domperidone, acotiamide, cinitapride, and placebo. Therefore, considering both efficacy and safety, cinitapride seems the preferred prokinetic agents for the treatment of FD.
Meanwhile, clinicians should pay close attention to the risk of abnormal blood levels of prolactin when administering acotiamide, as well as to the development of lower limb skin rash, mild lower abdominal pain, expressive galactorrhea, constipation, and hyperprolactinemia when prescribing domperidone. Nonetheless, these results also reflect the rarity of adverse events reported in RCTs. Observational studies with a larger sample size are required for more precise estimates of the risk of adverse events.
Overall, the quality of evidence for the outcome of total therapeutic efficacy and adverse events was moderate. Low to moderate risk of bias were rated across seven domains of the risk of bias assessment tool. In half of the included studies (14/28), the methods used for random sequence generation and allocation concealment were not clearly reported. The attrition bias and reporting bias were low across the included studies. Some studies (6/28) reported they used an ITT analysis to deal with missing data. For potential other bias, four studies reported that the study was funded by pharmaceutical industry however the funder was not involved in the research process [
3,
11,
12,
27].
This study was based on a previous systematic review [
2], and an update literature search was performed. Our study identified two RCTs relevant to cinitapride, a new prokinetic agent. Therefore, our findings will provide more information for clinicians to use when making decisions.
The study selection process in our study includes trials with varying sample sizes, methodologies and study populations. The potential heterogeneity in study designs and patient characteristics could impact the validity and generalizability of the observed treatment effects and adverse event profiles, which should be considered when discussing the practical applicability of the study’s findings to real-world clinical practice. We have tried our best to mitigate the impact of heterogeneity in this study. First, the updated search strategy was developed by an information specialist, which helped identify a greater number of studies, and only RCTs investigating the use of prokinetics in adult FD patients were included in this study to reduce the potential heterogeneity in study designs. Second, two review authors independently selected and extracted data, ensuring the transparency of the review process and the accuracy of the network meta-analysis. Third, rigorous and normative statistical analysis were carried out in each step in this meta-analysis, which is important for controlling the impact of heterogeneity. The exact impact of heterogeneity might be evaluated by subgroup analysis. However, for the included 28 RCTs, subgroup analysis for different study designs and patient characteristics could only include limited studies for each subgroup and lead to unreliable results. Moreover, the main purpose of this updated meta-analysis is to explore the totally efficacy and safety of prokinetics for FD. Subgroup analysis for heterogeneity in study designs and patient characteristics would be performed in the future as soon as possible when much more studies would be carried out, especially when enough number of studies and data focusing on each subgroup factor would be published.
This study also has several limitations. First, in the network meta-analysis, there is a small number of studies and participants in the cinitapride and metoclopramide group, which may underestimate the effect of these two interventions. The inconsistency between domperidone and mosapride, itopride and mosapride, itopride and domperidone, domperidone and placebo, itopride and placebo may also compromise the robustness and reliability of the network meta-analysis. Moreover, the definition of the total efficacy rate varies across studies, and different measurement criteria may also influence the accuracy of the network meta-analysis. Lastly, the Asia limited marketing of a number of prokinetics is a relevant limitation which impact generalizability of findings.
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