- Top of page
- Competing interests
Gastroesophageal reflux disease (GERD) is a common clinical disorder with an estimated prevalence of 10–28% in Europe and North America, and 2.5–6.7% in Asia [1–3]. Quality of life is significantly impaired in GERD patients with troublesome symptoms , and the associated socio-economic impact is enormous . Furthermore, GERD is associated with serious, albeit infrequent, complications such as haemorrhage, peptic stricture, specialized intestinal metaplasia of the oesophageal epithelium (Barrett's oesophagus) and oesophageal adenocarcinoma [5, 6].
Proton pump inhibitors (PPI), with proven therapeutic effectiveness [7, 8], are the current recommended pharmacotherapy for GERD [9–11]. However, not all treated patients achieve symptom relief [12, 13]. It has been noted that the symptoms of 40–50% of patients with non-erosive reflux disease (NERD) are not relieved with PPI [14, 15]. Although a greater therapeutic response to PPI is observed in patients with reflux oesophagitis (RE) when compared with NERD, some10–15% of RE patients experience PPI failure .
Prokinetic medication like mosapride, which effectively decreases episodes of gastro-oesophageal reflux, may theoretically be beneficial to GERD patients [16–18]. Although a prokinetic agent cannot be regarded as ideal monotherapy [8–10], its use as an adjunct to acid suppression has been suggested yet sparsely studied [9, 19–21]. Moreover, a recent non-randomized trial reported that patients with more severe pre-treatment symptoms benefited from the addition of mosapride to the standard dose of PPI .
This study aimed to investigate whether mosapride was more effective than placebo in achieving or maintaining symptom relief in RE patients who were already treated with a standard PPI regimen, i.e. lansoprazole. The subgroup of symptomatically severe patients was specifically examined.
- Top of page
- Competing interests
This study demonstrated that mosapride generally was not more effective than placebo as an adjunct to a standard dose of lansoprazole in ameliorating or controlling reflux symptoms in unselected RE patients. However, in those with severe reflux symptoms, combination therapy with lansoprazole and mosapride as compared with lansoprazole plus placebo resulted in greater symptom improvement after 4 weeks of treatment. FSSG symptom scores of >18 points may be a useful predictor for those who may benefit from combination therapy.
There is little evidence to support or refute the use of a prokinetic agent as an adjunct to adequate acid suppression in managing GERD patients [9–11]. As monotherapy, PPI is unequivocally superior to other medications either in relieving symptoms or in healing mucosal erosions in RE [7, 8], but whether combination therapy with a prokinetic drug is more effective has remained undetermined. In a randomized placebo-controlled trial comprising 61 GERD patients , Madan et al. reported that pantoprazole plus mosapride was more effective than pantoprazole plus placebo in resolving reflux symptoms in patients with RE (n= 32), but not in those with NERD (n= 29). In their trial, 18 out of 19 (94.7%) RE patients with combination therapy reported symptom resolution, a proportion significantly higher than those in the placebo group (6/13, 46.2%; P= 003). Nonetheless, it is worth noting that their participants were probably more severe or difficult to treat, inasmuch as the response rate after treatment with pantoprazole for 8 weeks was only 46.2%, remarkably lower than that observed in most previous studies .
Our finding that patients with higher pre-treatment symptom scores would maintain a greater symptom burden throughout study period (Table 2) was consistent with previous GERD studies, which have found that pretreatment symptom severity was a predictor for poor response to PPI. How to improve outcomes in this group of patients remains sparsely investigated. In a non-randomized trial evaluating efficacy of mosapride in GERD patients who remained dissatisfied after treatment for 12 weeks with PPI, Miyamoto and colleagues reported that patients with high pretreatment FSSG scores (17.4 ± 1.4) were more likely to respond poorly to monotherapy of PPI and to benefit from the addition of mosapride. However, effectiveness of mosapride over placebo could not be ascertained in their trial, which had no control group for comparison. In our double-blind placebo-controlled trial, mosapride plus PPI was more effective than placebo plus PPI in reducing symptom scores with a statistically significant mean difference of 5.34 points. Nonetheless, the magnitude of the 95% CI (0.28, 10.40) warned against an undisputable conclusion. Furthermore, although symptom scores have been frequently applied in gastrointestinal research that measures subjective symptomatic improvement, there remains controversy over the clinical relevance of symptom scores. Hence, results of this pilot study should be validated before they can be recommended in daily practice. Further statistically empowered randomized trials that include patients' global assessment of symptom relief as a study endpoint are now warranted.
Mosapride, a selective 5-hydroxytryptamine (5-HT) 4-receptor agonist, may alleviate GERD symptoms through its effect on oesophageal motility. Ruth et al. demonstrated mosapride to be more effective than placebo in decreasing reflux episodes and total acid exposure time in GERD patients [16, 17]. Cho et al. reported that mosapride effectively decreased bolus transit time and increased rates of total bolus transit in asymptomatic volunteers , a finding that implied the efficacy of mosapride in oesophageal acid clearance. In fact, before the era of PPI, a number of earlier studies had evaluated the role of cisapride, another 5-HT4-receptor agonist, in the management of GERD [25–27]. As a combination therapy, cisapride plus ranitidine has been shown to be more effective than ranitidine alone in maintaining symptom remission (66% vs. 49%, P= 0.05) in a randomized trial conducted by Vigneri and colleagues . Since cisapride has been withdrawn from clinical use because of its cardiovascular side effects, mosapride has become the 5-HT4-receptor agonist of choice and consequently was adopted in the current trial.
Decrease of symptom scores and the proportion of patients who maintain symptom control were chosen as primary outcomes for the first and second phase of the study, respectively, in order to reflect the characteristics of symptomatic responses to PPI in RE patients. Because treatment with lansoprazole for 4 weeks generally leads to significant symptom relief in responsive patients, it may be less appropriate to consider magnitude of symptom improvement as the study outcome in the second phase [28, 29]. Moreover, after receiving different study medications in the first phase, patients could not be regarded as comparable at entry to the second phase. A crossover design was deliberately chosen because if there had been therapeutic differences in the first phase, the results of the second phase would have been biased should the study medications have remained the same (expectancy effect) . An alternative way was to re-randomize the patients at entry to the second phase, thus generating four treatment arms. Regrettably, this study was not statistically empowered for a factorial design with four arms.
This study has the following strengths. First, the first phase of study was in essence a double-blind randomized trial, which eliminated probable bias and confounders. Second, inclusion of only symptomatic RE patients identified a clearly defined study population. NERD patients were not enrolled because they represent a more heterogeneous group of patients [31–33]. In addition, a subgroup analysis of severely symptomatic patients explored the interaction between treatment and baseline symptom severity. Because such patients who may benefit from combination therapy are not uncommon in general practice, our study has important clinical implications. Lastly, application of the validated FSSG symptom score as a means to distinguish clinically relevant subgroups is simple and objective.
Several limitations warrant discussion. First, the second phase was not a randomized trial in itself, because a crossover design was adopted to reduce the effect of ‘subject expectancy’. However, with a high response rate in either the mosapride or placebo group (86.64% vs. 82%, P= 0.401), any difference would have been clinically irrelevant. In any case, results of the first phase were not influenced despite this limitation. Second, whether or not adding mosapride to lansoprazole would hasten healing of erosive oesophagitis was not investigated. Because the rate of mucosal healing generally is higher and more predictable than that of symptom resolution in RE patients, this limitation may be of less clinical importance. Third, the negative result in the whole study sample with a size of 96 patients raises the concern of a type II error. Nonetheless, changes of symptoms scores between the two treatment arms were nearly identical in patients with baseline FSSG scores of 18 points or fewer (Figure 4). Therefore, the conclusion that mosapride was not more effective than placebo as an adjunct to a standard dose of PPI in RE patients is convincing. Finally, this study did not address the issue of maintenance therapy in the long term. It would be interesting to explore further whether mosapride has any role, combined with a low or standard dose of PPI, with a strategy of on-demand or continuous administration, in the long-term treatment of GERD.
In conclusion, our results do not support addition of mosapride to a standard dose of PPI in every RE patient, but indicates that mosapride as an adjunct to PPI may be beneficial in a subgroup of patients with severe symptoms.