To compare the one-week clinical effects of single doses of dexlansoprazole and esomeprazole on grades A and B erosive esophagitis.

We enrolled 175 adult patients with gastroesophageal reflux disease (GERD). The patients were randomized in a 1:1 ratio into two sequence groups to define the order in which they received single doses of dexlansoprazole (n = 88) and esomeprazole (n = 87) for an intention-to-treat analysis. The primary end-points were the complete symptom resolution (CSR) rates at days 1, 3, and 7 after drug administration.

Thirteen patients were lost to follow-up, resulting in 81 patients in each group for the per-protocol analysis. The CSRs for both groups were similar at days 1, 3 and 7. In the subgroup analysis, the female patients achieved higher CSRs in the dexlansoprazole group than in the esomeprazole group at day 3 (38.3% vs 18.4%, P = 0.046). An increasing trend toward a higher CSR was observed in the dexlansoprazole group at day 7 (55.3% vs 36.8%, P = 0.09). In the esomeprazole group, female sex was a negative predictive factor for CSR on post-administration day 1 [OR = -1.249 ± 0.543; 95%CI: 0.287 (0.099-0.832), P = 0.022] and day 3 [OR = -1.254 ± 0.519; 95%CI: 0.285 (0.103-0.789), P = 0.016]. Patients with spicy food eating habits achieved lower CSRs on day 1 [37.3% vs 21.4%, OR = -0.969 ± 0.438; 95%CI: 0.380 (0.161-0.896), P = 0.027].

The overall CSR for GERD patients was similar at days 1-7 for both the dexlansoprazole and esomeprazole groups, although a higher incidence of CSR was observed on day 3 in female patients who received a single dose of dexlansoprazole.

Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder worldwide. GERD continues to increase in incidence with the aging population and the obesity epidemic[1,2]. Based on the Montreal definition, GERD is diagnosed when the reflux of stomach contents causes troublesome symptoms[3], such as heartburn and regurgitation, as well as other atypical or extraesophageal symptoms, such as chest pain, asthma, voice hoarseness, and sleep disturbance[4]. Proton pump inhibitors (PPIs) are widely recognized as superior to other antisecretory therapies, including histamine-2 receptor antagonists (H₂RA), and thus play a critical role in pharmacological therapy for the treatment of GERD[5]. Although PPIs represent the mainstay of treatment for healing erosive esophagitis, symptom relief, and preventing complications, several studies have shown that up to 40% of GERD patients report either a partial or a complete lack of response of their symptoms after taking a standard once-daily PPI dose[6-8].

A study comparing the pharmacokinetic effects of different PPIs 12-24 h post-dose showed that the mean percentage of time with a pH > 4 and the average of the pH mean were greater for dexlansoprazole than for esomeprazole (60% vs 42%, P < 0.001 and pH 4.5 vs 3.5, P < 0.001). However, this study did not report the clinical effects after the use of tablets[9]. Rapid onset PPIs for fast symptom relief is an unmet need in GERD treatment. To date, no reports have investigated the differences in short-term clinical effects and timing to symptom relief of GERD between dexlansoprazole 60 mg and esomeprazole 40 mg. Therefore, we conducted a randomized, controlled, open-label study to compare the 7-d clinical effects of single doses of dexlansoprazole (60 mg) and esomeprazole (40 mg) in patients with Los Angeles (LA) grades A and B erosive esophagitis.

From April 2014 to March 2016, two hundred and forty-three eligible symptomatic patients who had endoscopy-confirmed Los Angeles grade A or B erosive esophagitis were assessed. A total of 175 of these patients were recruited for randomization after excluding 68 patients who refused enrollment (n = 40), cancer patients (n = 19), and patients with advanced liver disease (n = 3), end-stage renal disease (n = 4), and coronary heart disease (n = 2). A total of 88 patients received the dexlansoprazole treatment, and 87 patients received the esomeprazole treatment. A total of 13 patients were lost during the follow-up period (seven in the dexlansoprazole group and 6 in the esomeprazole group) (Figure 1). The baseline characteristics of the two groups were similar in age, sex, diet habits, body mass index, and symptom scores (GERDQ) (Table 1). At days 1, 3, and 7 post-dose, the CSR rates for the dexlansoprazole vs esomeprazole groups were 25.9% vs 28.4% (P = 0.724), 33.3% vs 32.1% (P = 0.867), and 51.9% vs 48.1% (P = 0.637), respectively. The symptoms and frequencies of nighttime reflux were similar in both groups (Table 2). In the subgroup analysis based on sex, females had higher CSR rates in the dexlansoprazole group at day 3 (38.3% vs 18.4%, P = 0.046), and an increasing trend was observed at day 7 (55.3% vs 36.8%, P = 0.09) (Table 3). However, no significant differences were observed in the subgroup analyses based on age and body weight. After splitting the data from the two PPI groups in the multivariate analysis, no dependent factor for CSR was found in the dexlansoprazole group (Table 4). In the esomeprazole group, female sex was a negative predictive factor for CSR at post-dose days 1 [OR = -1.249 ± 0.543; 95%CI: 0.287 (0.099-0.832), P = 0.022] and 3 [OR = -1.254 ± 0.519; 95%CI: 0.285 (0.103-0.789), P = 0.016]. In addition, patients with a habit of consuming spicy foods had lower CSR rates (37.3% vs 21.4%) on day 1 after the multivariate analysis [OR = -0.969 ± 0.438; 95%CI: 0.380 (0.161-0.896), P = 0.027] (Table 5). No dependent factor was found on days 3 and 7.

We conducted a randomized, controlled, open-label study to compare the 7-d clinical effects of single doses of dexlansoprazole 60 mg and esomeprazole 40 mg for GERD patients. We observed that the overall CSR rates for GERD patients were similar at days 1 through 7 of treatment for both the dexlansoprazole and esomeprazole groups. However, in our subgroup analysis based on sex, we observed that females had higher CSR rates in the dexlansoprazole group at day 3 (38.3% vs 18.4%, P = 0.046), and an increasing trend was observed at day 7 (55.3% vs 36.8%, P = 0.09). The logistic regression analysis showed that female sex was a negative predictive factor for CSR on post-dose days 1 [OR = -1.249 ± 0.543; 95%CI: 0.287 (0.099-0.832), P = 0.022] and 3 [OR = -1.254 ± 0.519; 95%CI: 0.285 (0.103-0.789), P = 0.016] in the esomeprazole group. We also found that patients with the habit of eating spicy foods had lower CSR rates (37.3% vs 21.4%) on day 1 after the multivariate analysis [OR = -0.969 ± 0.438; 95%CI: 0.380 (0.161-0.896), P = 0.027].

Both dexlansoprazole and esomeprazole are potent PPIs for gastric acid suppression with excellent symptom relief for patients with GERD[14-19]. The advantage of dexlansoprazole MR (Takeda Pharmaceuticals, Osaka, Japan) is that it employs a novel approach by which its dual delayed-release (DDR) formulation prolongs the plasma concentration and ultimately extends the duration of acid suppression[14], thereby offering a twice-daily dosing effect in a one-time dose. Metz et al[15] found that patients who received a 60-mg dose of dexlansoprazole MR satisfactorily controlled heartburn (median of 91%-96% for 24-h heartburn-free days and 96%-99% for heartburn-free nights). Moreover, Sharma et al[16] reported that 92%-95% of patients were healed using dexlansoprazole MR for 8 wk. Conversely, esomeprazole (40 mg) is a delayed-release formulation with single-release characteristics that produces maximum plasma concentrations at approximately 1.6 h post-dose. Approximately 73%-75% heartburn-free days and 85%-91% heartburn-free nights were observed in patients who received 40 mg of esomeprazole for 4 wk[17-19]. In addition, esomeprazole at 40 mg/d also achieved good healing rates (87%-94.1%) for erosive esophagitis after 8 wk of treatment[18-20].

However, no direct head-to-head comparative report has investigated the short-term clinical effects or timing to symptom relief of GERD between dexlansoprazole at 60 mg and esomeprazole at 40 mg. Wu et al[21] reported an indirect comparative study that revealed that the dexlansoprazole 30 mg dose was more effective than esomeprazole at the 20 mg or 40 mg dose (RR = 2.01, 95%CI: 1.15-3.51; RR = 2.17, 95%CI: 1.39-3.38, respectively) for patients with non-erosive esophagitis at 4 wk. However, no significant differences were found in the healing rates of erosive esophagitis. A one-day comparative pH study showed that dexlansoprazole had a higher mean percentage of time with a pH > 4 than esomeprazole (58% and 48%, P = 0.003) at 0-24 h post-dose[9]. Unfortunately, differences in the clinical effects between these two PPIs were not mentioned.

In this study, we found that the symptoms and frequencies of nighttime reflux were similar between the dexlansoprazole and esomeprazole groups (P = 0.787 and P = 0.343, respectively). At days 1, 3, and 7 post-dose, the CSR rates between the two groups were similar (25.9% vs 28.4%, P = 0.724, 33.3% vs 32.1%, P = 0.867, and 51.9% vs 48.1%, P = 0.637, respectively). Nevertheless, we also observed that female patients had higher CSR rates in the dexlansoprazole group (P = 0.046) and an increasing trend for the effect on day 7 (P = 0.09) when we performed the subgroup analysis based on sex. Remarkably, our logistic regression analysis showed that female sex was a negative predictive factor for CSR on post-dose days 1 [OR = -1.249 ± 0.543; 95%CI: 0.287 (0.099-0.832), P = 0.022] and 3 [OR = -1.254 ± 0.519; 95%CI: 0.285 (0.103-0.789), P = 0.016] in the esomeprazole group. These findings implied that esomeprazole at 40 mg required more time (3 d) than dexlansoprazole at 60 mg to attain CSR in females. Several possible mechanisms may underlie these observations. First, both esomeprazole and dexlansoprazole are extensively metabolized in the liver by oxidation, reduction, and subsequent conversion of sulfate, glucuronide and glutathione conjugates to inactive metabolites. Oxidative metabolites are formed by the cytochrome P450 (CYP) enzyme system, mainly by CYP2C19 and CYP3A4[22,23]. In the pharmacokinetics report of esomeprazole[24], the mean exposure (AUC) to esomeprazole increases from 4.32 μmol·h/L on day 1 to 11.2 μmol·h/L on day 5 after a 40-mg once-daily dose, indicating that the pharmacokinetics of esomeprazole are time- and dose-dependent[25]. For dexlansoprazole[26,27], no accumulation of dexlansoprazole occurs after multiple once-daily doses of 60 mg, although the mean AUC and max concentration (Cmax) values of dexlansoprazole are slightly higher (less than 10%) on day 5 than on day 1. We validated this finding by calculating the Cmax of dexlansoprazole, which was 16 μmol·h/L on day 1 and 17.67 μmol·h/L on day 5. As a result, dexlansoprazole almost achieved the target concentration on day 1. Second, ample evidence has shown that estrogen and progestogen can enhance relaxation of the lower esophageal sphincters and induce GERD symptoms[28-30], especially in post-menopausal women taking hormone replacement therapy (HRT)[31-36]. These hypotheses might explain why female patients taking esomeprazole needed at least 3 more days to accumulate a sufficient plasma concentration to achieve plateau levels and desirable clinical effects.

Another observation in this study was the lower CSR rates in patients with the habit of eating spicy foods in the esomeprazole group at day 1 after the multivariate analysis. No reliable data are available in the existing literature regarding the role of diet or specific foods or drinks in GERD[37]. Some foods are believed to induce or worsen GERD symptoms in daily clinical practice, and this belief has led to advising patients to avoid the suspect foods[38]. Nebel et al[39] demonstrated that fried foods, spicy foods, and alcohol were the most common precipitating factors of heartburn, but this study had no control group and did not quantify the intake of dietary items. In contrast, our study used a dietary questionnaire to estimate the frequency of the consumption of different types of food.

In addition to the above shortcoming, this study has other limitations. First, we enrolled only patients with Los Angeles grade A or B erosive esophagitis in this study and not those with Los Angeles grade C or D erosive esophagitis or Barrett’s esophagus. As a result, the study may not represent the clinical effects of the entire GERD population. Second, this study used dietary questionnaires to estimate the frequency of consumption of different types of foods but did not quantify the fat or carbohydrate content. Nonetheless, this pilot study is the first important report to compare the clinical efficacy of a one-week dual delayed-release treatment with dexlansoprazole at 60 mg and esomeprazole at 40 mg for grades A and B GERD patients, since fast symptomatic relief is an important unmet need in the treatment of GERD.

In conclusion, the overall CSR rates for GERD were similar at days 1 through 7 for both the dexlansoprazole and esomeprazole groups, although a higher CSR was observed at day 3 in female patients who received a single dose of dexlansoprazole. Since rapid onset of proton-pump inhibitors for fast symptom relief is an unmet need for the treatment of GERD and no report have investigated the short-term clinical effects of dexlansoprazole 60 mg vs esomeprazole 40 mg, this finding of this pilot study is novel. Furthermore, these findings may have important implications for clinical practice when treating patients with grades A and B GERD. This issue was hampered by the small sample size. Thus, we believe that large-scale comparative studies are necessary.