Functional dyspepsia (FD) is a clinical syndrome defined as the presence of symptoms thought to originate from the gastroduodenal region in the absence of organic, systemic, or metabolic disease likely to explain the symptoms [
The primary treatment options to FD may include gastric acid suppression and gastroduodenal prokinetic agents, and some other drugs may also be applied. The Rome III consensus suggested that EPS might respond to the acid-suppressive or antacid therapy and PDS might respond to the prokinetic or motility-modifying treatment [
Acotiamide is a new prokinetic agent which exerts its gastroprokinetic activity by enhancement of acetylcholine release via acting as an antagonist on the M1 and M2 muscarinic receptors in the enteric nervous system and inhibiting acetylcholinesterase activity [
This study was conducted to summarize the current evidence and systematically and critically evaluate the efficacy as well as its adverse effects of acotiamide in the treatment of patients with FD.
MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, BIOSIS Previews,
Randomized controlled trials (RCTs) evaluating the efficacy of acotiamide compared with placebo in patients with FD were included. Duplicate publications or studies in which raw data of interest cannot be extracted were excluded. Two reviewers screened the identified studies for eligibility independently, with disagreements resolved by consensus.
Data of eligible studies were extracted according to the intention-to-treat criteria by two reviewers independently using a standardized data collection form, and differences were resolved by discussion. If necessary, a third reviewer was consulted to reach consensus. Trial investigators were requested for additional unpublished data as needed. Data extracted included study design, publication details, patient characteristics (number of patients, age, gender, and dyspepsia symptoms), diagnostic criteria, treatment regimen (dose and duration), outcome measures, and study outcomes.
The quality of each eligible study was assessed by two reviewers separately using a modified Jadad scoring system [
The primary endpoint was to assess the efficacy of acotiamide compared with placebo for the overall improvement of FD symptoms. Secondary endpoints included evaluating the efficacy of acotiamide for the treatment of PDS and EPS and for the elimination of individual FD symptoms when possible. Adverse events which might be related to the therapy were evaluated as well. Subgroup analyses based on the different doses of acotiamide were conducted to explore the potentially optimal dose of acotiamide in the treatment of FD.
To estimate the efficacy of intervention, pooled risk ratio (RR) together with 95% confidential interval (CI) was calculated by the Mantel-Haenszel fixed-effect model if no significant heterogeneity was detected. When significant heterogeneity existed, a random-effects model was used to calculate the summary RR with 95% CI. Heterogeneity among studies was assessed using Cochran’s
The study selection process is summarized in Figure
Flow diagram of study identification and selection.
One publication reported two RCTs [
Main characteristics of eligible studies.
Author, year | Location, |
Publication |
Diagnostic criteria | Number of patients | Dose of |
Duration of |
Jadad |
---|---|---|---|---|---|---|---|
Kusunoki et al. |
Japan, 1 site | Full text | Rome II criteria | 42 | 100 mg, tid | 14–18 d | 4 |
Matsueda et al. |
Japan, 33 sites | Full text | Rome II criteria | 323 | 100 mg |
4 w | 5 |
Matsueda et al. |
Japan, 46 sites | Full text | Rome II criteria | 462 | 50 mg, 100 mg |
4 w | 5 |
Tack et al. |
Europe, 8 sites | Full text | Rome II criteria | 71 | 50 mg, 100 mg |
3 w | 4 |
Talley et al. |
USA, 59 sites | Meeting |
Rome II criteria | 416 | 300 mg, 600 mg |
12 w | 3 |
Matsueda et al. |
Japan, NR | Meeting |
Patients with FD symptoms and negative endoscopy | 127 | 50 mg, 100 mg |
4 w | 2 |
Matsueda et al. |
Japan, 67 sites | Full text | Rome III criteria | 897 | 100 mg, tid | 4 w | 5 |
FD, functional dyspepsia; NR, not reported; RCT, randomized controlled trial; and tid, three times daily.
A total of 6 trials reported the overall improvement of FD symptoms using OTE or PGSI as the endpoint, consisting of 2267 FD patients (acotiamide, 1442; placebo, 825) [
Pooled RR of overall improvement of FD symptoms in patients receiving acotiamide versus placebo.
Funnel plot analysis. Funnel plot and Egger’s test showed no evidence of publication bias.
Subgroup analyses of different doses of acotiamide showed that the 100 mg group significantly improved the symptoms of the acotiamide group compared with the placebo group without significant heterogeneity (RR, 1.39; 95% CI, 1.24–1.56,
Pooled analysis of the efficacy of acotiamide in the improvement of PDS yielded a summary RR of 1.29 (95% CI, 1.09–1.53,
Pooled RR of acotiamide versus placebo for elimination of FD symptoms by Mantel-Haenszel fixed-effect model.
Groups and subgroups | Number of trials [reference] | Number of patients | RR; 95% CI |
|
Test of heterogeneity | |
---|---|---|---|---|---|---|
|
| |||||
PDS | 2 [ |
396 | 1.29; 1.09–1.53 | 0.003 | 0.830 | 0% |
50 mg, tid | 1 [ |
151 | 1.08; 0.76–1.53 | 0.660 | NA | NA |
100 mg, tid | 2 [ |
206 | 1.41; 1.07–1.85 | 0.010 | 0.860 | 0% |
300 mg, tid | 2 [ |
218 | 1.33; 1.01–1.75 | 0.040 | 0.960 | 0% |
EPS | 2 [ |
320 | 0.92; 0.76–1.11 | 0.390 | 0.970 | 0% |
50 mg, tid | 1 [ |
73 | 0.88; 0.58–1.34 | 0.550 | NA | NA |
100 mg, tid | 2 [ |
184 | 0.96; 0.72–1.29 | 0.800 | 0.520 | 0% |
300 mg, tid | 2 [ |
192 | 0.90; 0.67–1.21 | 0.480 | 0.990 | 0% |
Postprandial fullnessa | 3 [ |
1438 | 1.90; 1.37–2.64 | <0.001 | 0.030 | 60% |
50 mg, tid | 1 [ |
149 | 3.19; 1.36–7.44 | 0.007 | NA | NA |
100 mg, tid | 3 [ |
1190 | 1.75; 1.14–2.66 | 0.010 | 0.060 | 64% |
300 mg, tid | 2 [ |
337 | 2.05; 0.79–5.34 | 0.140 | 0.040 | 77% |
Upper abdominal bloating | 3 [ |
1232 | 1.30; 1.12–1.50 | <0.001 | 0.930 | 0% |
50 mg, tid | 1 [ |
135 | 1.26; 0.79–2.01 | 0.330 | NA | NA |
100 mg, tid | 3 [ |
1001 | 1.29; 1.08–1.54 | 0.005 | 0.550 | 0% |
300 mg, tid | 2 [ |
310 | 1.34; 0.99–1.80 | 0.060 | 0.730 | 0% |
Early satiety | 3 [ |
1206 | 1.39; 1.19–1.61 | <0.001 | 0.830 | 0% |
50 mg, tid | 1 [ |
133 | 1.60; 0.95–2.70 | 0.080 | NA | NA |
100 mg, tid | 3 [ |
1002 | 1.39; 1.16–1.67 | <0.001 | 0.450 | 0% |
300 mg, tid | 2 [ |
285 | 1.29; 0.94–1.76 | 0.110 | 0.830 | 0% |
aMantel-Haenszel random-effects model.
CI, confidential interval; FD, functional dyspepsia; NA, not applicable; RR, risk ratio; and tid, three times daily.
As shown in Table
Pooled RR of acotiamide versus placebo for nonresponders by Mantel-Haenszel fixed-effect model.
Groups or subgroups | Number of trials [reference] | Number of patients | RR; 95% CI |
|
Test of heterogeneity | |
---|---|---|---|---|---|---|
|
| |||||
Overall symptoms | 2 [ |
768 | 0.95; 0.73–1.24 | 0.710 | 0.510 | 0% |
50 mg, tid | 1 [ |
227 | 1.46; 0.78–2.73 | 0.230 | NA | NA |
100 mg, tid | 2 [ |
431 | 0.83; 0.55–1.26 | 0.380 | 0.420 | 0% |
300 mg, tid | 2 [ |
441 | 0.90; 0.60–1.34 | 0.590 | 0.590 | 0% |
PDS | 2 [ |
396 | 0.71; 0.50–1.02 | 0.060 | 0.300 | 18% |
50 mg, tid | 1 [ |
151 | 1.22; 0.64–2.34 | 0.540 | NA | NA |
100 mg, tid | 2 [ |
206 | 0.51; 0.26–0.99 | 0.050 | 0.370 | 0% |
300 mg, tid | 2 [ |
218 | 0.61; 0.34–1.10 | 0.100 | 0.560 | 0% |
EPSa | 2 [ |
320 | 1.76; 0.90–3.45 | 0.100 | 0.190 | 35% |
50 mg, tid | 1 [ |
73 | 3.89; 0.46–33.17 | 0.210 | NA | NA |
100 mg, tid | 2 [ |
184 | 1.91; 0.48–7.57 | 0.360 | 0.170 | 47% |
300 mg, tid | 2 [ |
192 | 2.31; 0.34–15.74 | 0.390 | 0.070 | 70% |
aMantel-Haenszel random-effects model.
CI, confidential interval; FD, functional dyspepsia; NA, not applicable; RR, risk ratio; and tid, three times daily.
The pooled elimination efficacy of acotiamide in patients with postprandial fullness, upper abdominal bloating, and early satiety are presented in Table
The pooled estimates of common adverse events reported in the included trials are presented in Table
Pooled RR of adverse events in FD patients receiving acotiamide versus placebo by Mantel-Haenszel fixed-effect model.
Groups | Number of trials [reference] | Number of patients | RR; 95% CI |
|
Test of heterogeneity | |
---|---|---|---|---|---|---|
|
| |||||
Serum prolactin increaseda | 4 [ |
1709 | 1.59; 0.79–3.21 | 0.190 | 0.120 | 40% |
Alanine aminotransferase increased | 4 [ |
1709 | 1.42; 0.82–2.47 | 0.210 | 0.710 | 0% |
Triglycerides increased | 3 [ |
1667 | 0.89; 0.69–1.14 | 0.360 | 0.810 | 0% |
|
3 [ |
1667 | 1.01; 0.66–1.54 | 0.970 | 0.630 | 0% |
White blood cell count increased | 1 [ |
892 | 0.65; 0.34–1.27 | 0.210 | NA | NA |
Serum bilirubin increased | 1 [ |
892 | 1.04; 0.55–1.95 | 0.910 | NA | NA |
Constipation | 2 [ |
775 | 0.99; 0.34–2.92 | 0.980 | 0.620 | 0% |
Diarrhoea | 3 [ |
1667 | 1.34; 0.81–2.23 | 0.250 | 0.860 | 0% |
Nasopharyngitis | 1 [ |
892 | 0.93; 0.61–1.42 | 0.750 | NA | NA |
aMantel-Haenszel random-effects model.
CI, confidential interval; FD, functional dyspepsia; NA, not applicable; and RR, risk ratio.
This systematic review and meta-analysis has investigated the efficacy as well as adverse effects of a new drug, acotiamide, in the treatment of patients with FD. The results indicated that acotiamide could improve the FD symptoms, mainly symptoms of patients with PDS, compared with the placebo, with a quantitatively small but statistically significant summary RR compared with the placebo. Acotiamide was well tolerated during therapy without significantly increasing the adverse events in the studies reporting these data.
The OTE and PGSI assessments were used to evaluate the overall efficacy of acotiamide for relief of FD symptoms in some included studies [
The beneficial effect of acotiamide in patients with FD was also supported by other efficacy endpoints. Quality of life of FD patients treated with acotiamide was assessed by the SF-36 questionnaire [
The results of our meta-analysis showed that acotiamide could be effective in the treatment of patients with PDS. And the elimination rates of three individual cardinal symptoms of PDS including postprandial fullness, upper abdominal bloating, and early satiety were significantly higher in the acotiamide groups than that in the placebo groups. The pathophysiological mechanisms associated with these PDS symptoms are mainly delayed gastric emptying and impaired gastric accommodation [
The subgroup analyses of our study suggested that the dose of acotiamide 100 mg tid showed a consistent efficacy not only for the overall improvement of FD symptoms but also for the elimination of individual cardinal symptoms of PDS in FD patients. The relatively high improvement rate of FD symptoms by acotiamide 100 mg tid found in a multicenter, single-arm, long-term (48 weeks), phase III study [
The incidences of adverse events were not significantly different between the acotiamide groups and placebo groups in our analysis. Acotiamide was well tolerated, and most adverse events reported in the included studies were mild or moderate. No clinical changes in vital signs or electrocardiographic variables were reported. Acotiamide has no affinity for the hERG channel [
There were several limitations to our meta-analysis, which need to be taken seriously when interpreting the results from this study. First, the present study possesses the inherent limitations associated with the methods of meta-analysis. Second, although the endpoints used in the included studies such as OTE and PGSI have the advantages mentioned above, these endpoints require patients’ recall of the pretreatment symptom severity, which may induce bias. And aggravation of one or more specific symptoms may not be adequately identified by an overall endpoint [
In summary, our study suggests that acotiamide has the potential to improve the symptoms of patients with FD, particularly of patients with PDS, with a quantitatively small but statistically significant summary RR compared with the placebo, without major adverse effects. The dosage of acotiamide 100 mg three times daily seems to be the appropriate dose in the treatment of FD.
As the absolute benefit of acotiamide over placebo seems to be modest although statistically significant, and no apparent dose-response relationship between different dosages of acotiamide and the improvement of FD symptoms was found, more convincing evidence is needed to establish the efficacy of acotiamide in the treatment of FD. And most studies investigating the efficacy of acotiamide have been conducted in Japan so far; more studies from other parts of the world could help to confirm the efficacy of acotiamide in other populations. Future researches are needed to also investigate the long-lasting beneficial effects of acotiamide to prevent the relapse of FD and the long-term safety and tolerability profiles in large-scale, high quality clinical trials. Factors predicting a good response to acotiamide in the individual patient and the most appropriate treatment length also need further investigation.
Confidential interval
Epigastric pain syndrome
Functional dyspepsia
Overall treatment efficacy
Postprandial distress syndrome
Patient’s global symptomatic improvement
Randomized controlled trials
Risk ratio
Three times daily.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors would like to thank Dr. H. Kato (Department of Clinical Research, Zeria Pharmaceutical Co., Ltd., Tokyo, Japan) and Dr. K. Matsueda (Sakura Life Clinic, Kinshi, Sumida, Tokyo, Japan) for their generosity in providing supplementary data of their studies, and Professor J. Tack (Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium) for providing some other help.