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Prokinetics for the Treatment of Functional Dyspepsia: Bayesian

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Prokinetics for the Treatment of Functional Dyspepsia: Bayesian Yang et al. BMC Gastroenterology (2017) 17:83 DOI 10.1186/s12876-017-0639-0 RESEARCH ARTICLE Open Access Prokinetics for the treatment of functional dyspepsia: Bayesian network meta-analysis Young Joo Yang, Chang Seok Bang* , Gwang Ho Baik, Tae Young Park, Suk Pyo Shin, Ki Tae Suk and Dong Joon Kim Abstract Background: Controversies persist regarding the effect of prokinetics for the treatment of functional dyspepsia (FD). This study aimed to assess the comparative efficacy of prokinetic agents for the treatment of FD. Methods: Randomized controlled trials (RCTs) of prokinetics for the treatment of FD were identified from core databases. Symptom response rates were extracted and analyzed using odds ratios (ORs). A Bayesian network meta- analysis was performed using the Markov chain Monte Carlo method in WinBUGS and NetMetaXL. Results: In total, 25 RCTs, which included 4473 patients with FD who were treated with 6 different prokinetics or placebo, were identified and analyzed. Metoclopramide showed the best surface under the cumulative ranking curve (SUCRA) probability (92.5%), followed by trimebutine (74.5%) and mosapride (63.3%). However, the therapeutic efficacy of metoclopramide was not significantly different from that of trimebutine (OR:1.32, 95% credible interval: 0.27–6.06), mosapride (OR: 1.99, 95% credible interval: 0.87–4.72), or domperidone (OR: 2.04, 95% credible interval: 0.92–4.60). Metoclopramide showed better efficacy than itopride (OR: 2.79, 95% credible interval: 1. 29–6.21) and acotiamide (OR: 3.07, 95% credible interval: 1.43–6.75). Domperidone (SUCRA probability 62.9%) showed better efficacy than itopride (OR: 1.37, 95% credible interval: 1.07–1.77) and acotiamide (OR: 1.51, 95% credible interval: 1.04–2.18). Conclusions: Metoclopramide, trimebutine, mosapride, and domperidone showed better efficacy for the treatment of FD than itopride or acotiamide. Considering the adverse events related to metoclopramide or domperidone, the short-term use of these agents or the alternative use of trimebutine or mosapride could be recommended for the symptomatic relief of FD. Keywords: Comparative effectiveness research, Functional dyspepsia, Network meta-analysis, Systematic review, Prokinetics Background into two distinct conditions, which are postprandial Functional dyspepsia (FD) is a common condition in distress syndrome, associated with meal-induced clinical practice [1]. According to the Rome III and IV bothersome fullness or early satiation, and epigastric criteria, FD is defined as the presence of at least one of pain syndrome, showing bothersome epigastric pain the following symptoms; postprandial fullness, early or burning [2, 3]. satiation, epigastric pain or burning, without evidence of This condition involves complex pathophysiologic structural disease to explain the symptoms fulfilling time mechanisms and shares overlapping symptoms with criteria for the last three months with symptom onset at gastroesophageal reflux disease or other functional least six months before diagnosis and a frequency of at gastrointestinal disorders. The mainstay of the treatment least three days per week [2, 3]. FD is subcategorized of FD has been to target gastric acid secretion and im- paired gut motility. The role of acid inhibitory drugs in the treatment of FD is well established [4]. In a subtype * Correspondence: [email protected] Department of Internal Medicine, Hallym University College of Medicine, of FD, the response rate of epigastric pain syndrome to Chuncheon Sacred Heart Hospital, Sakju-ro 77, Chuncheon, Gangwon-do 24253, Republic of Korea © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yang et al. BMC Gastroenterology (2017) 17:83 Page 2 of 11 acid inhibitory therapy is known to be better than that The abstracts of all identified studies were reviewed to of post-prandial distress syndrome [5]. exclude irrelevant articles. Full-text review was per- Excluding acid inhibitory therapy, prokinetics are the formed to determine whether the inclusion criteria were mainstay of the treatment of FD. However, the role of satisfied by the remaining studies. Disagreements be- prokinetics has not been well established, and inconsist- tween the two evaluators were resolved by discussion or ent results have been reported regarding the therapeutic by consultation with a third author (D.J.K.). efficacy of each drug [6–10]. Moreover, previously pub- lished pairwise meta-analyses were conducted by exam- Assessment of methodological quality ining several drugs with different mechanisms of action The methodological quality of the enrolled studies was as a single group, which cannot present the efficacy of assessed using the Risk of Bias table (RoB). The RoB was each prokinetic agent [8, 9]. However, head-to-head assessed as described in the Cochrane handbook by re- efficacy comparison of prokinetic agents in the treat- cording the method used to generate the randomization ment of FD is not easy and pooled comparative efficacy sequence, allocation concealment, the determination of has not been established. whether blinding was implemented for participants or Unlike traditional pair-wise meta-analysis, network staff, and whether there was evidence of selective reporting meta-analysis enables comparing more than 2 treat- of the outcomes [12]. Review Manager version 5.3.3 (Rev- ments strengthening the precision in the estimate and man for Windows 7, the Nordic Cochrane Centre, presenting relative effect sizes in a rank order [11]. Copenhagen, Denmark) was used to generate the RoB Therefore, this study aimed to evaluate the comparative table. Two of the authors (C.S.B. and G.H.B.) independently effectiveness of each prokinetic in the treatment of FD evaluated the methodological quality of all studies, and any using an indirect comparison method. disagreements between the two evaluators were resolved by discussion or by consultation with a third author (D.J.K.). Methods Literature search Statistical analysis A systematic review was conducted using electronic We investigated the efficacy of prokinetics for the treat- databases. MEDLINE (PubMed), EMBASE, and the ment of FD using odds ratios (ORs). We calculated the Cochrane Central Register of Controlled Trials (CEN- ORs based on an intention-to-treat analysis, when possible, TRAL) in the Cochrane Library were searched using from the original articles to compare the efficacy of proki- common keywords related to FD and prokinetics (incep- netics for the treatment of FD. Network meta-analyses tion to July 2015). The keywords were as follows: ‘func- were conducted using the Bayesian Markov Chain Monte tional dyspepsia’, ‘prokinetics’, ‘mosapride’, ‘itopride’, Carlo method in WinBUGS 1.4.3 (MRC Biostatistics Unit, ‘trimebutine’, ‘metoclopramide’, ‘domperidone’, and ‘aco- Cambridge, and Imperial College School of Medicine, tiamide’, drawn from MeSH or Emtree terminology and London, UK) and Microsoft-Excel-based network meta- using Boolean operators. Only publications involving analysis tool (NetMetaXL) [11]. Effect sizes for the human subjects were searched. The bibliographies of Bayesian network meta-analysis were described with 95% relevant articles were also reviewed to identify additional credible interval. Statistical validity is guaranteed when the studies. The language of publication was not restricted 95% credible interval does not include 1. The detailed data and all publications except Korean and English were input form and initial data for the analysis of network translated using commercial translation service. meta-analysis can be found in the Additional file 1. Selection criteria Results We included only randomized controlled trials (RCTs) Identification of relevant studies meeting all of the following criteria: 1) designed to Figure 1 shows a flow diagram of how relevant studies evaluate FD in the target or control group; 2) included a were identified. A total of 946 articles were identified by group that was given prokinetics and a comparison searching 3 core databases and by hand searching the group that was given placebo or other prokinetics; and relevant bibliographies. In all, 307 duplicate articles and 3) presented comparative outcomes about symptomatic an additional 550 articles were excluded during the ini- relief rates of FD after treatment. Exclusion criteria were tial screening after reviewing the titles and abstracts. as follows: 1) incomplete data or 2) review article. The full texts of the remaining 89 articles were thor- oughly reviewed. Among these studies, 63 were excluded Selection of relevant studies from the final analysis. The reasons for the exclusion of Two of the authors (C.S.B. and G.H.B.) independently studies during the final review were as follows: review evaluated the eligibility of all studies retrieved from the article (n = 19) or incomplete data (n = 45). The databases based on the predetermined selection criteria. remaining 25 RCTs were included in the final analysis. Yang et al. BMC Gastroenterology
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