Published online Dec 21, 2017. doi: 10.3748/wjg.v23.i47.8395
Peer-review started: July 28, 2017
First decision: August 30, 2017
Revised: September 19, 2017
Accepted: September 26, 2017
Article in press: September 26, 2017
Published online: December 21, 2017
Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder worldwide and continues to increase in incidence due to the aging population and obesity epidemic. Although proton pump inhibitors (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. Rapid onset proton-pump inhibitors for fast symptom relief is an unmet need for GERD treatment. To date, no reports have investigated the short-term clinical effects and timing to symptom relief of gastroesophageal reflux disease (GERD) between dexlansoprazole (60 mg) and esomeprazole (40 mg). This report is the first randomized, controlled, open-label study to compare the 7-d clinical effects of single doses of dexlansoprazole at 60 mg and esomeprazole at 40 mg for LA grades A and B erosive esophagitis.
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. Therefore, the significance of solving these problems for future research in this field should be based on large-scale, head-to-head comparisons of these PPIs on immediate symptom relief for GERD to fulfill the unmet need in real-world treatment.
The main objectives realized in this study motivated us to conduct this randomized, controlled, open-label study that compared the 7-d clinical effects of single doses of dexlansoprazole at 60 mg and esomeprazole at 40 mg for LA grades A and B erosive esophagitis.
This study was funded by the Research Foundation of the Chang Gung Memorial Hospital, Taiwan (CMRPG8D1441), and has been registered in a publicly accessible registry (ClinicalTrials.gov number: NCT03128736). We enrolled 175 adult GERD subjects and randomized them in a 1:1 ratio into two sequence groups that defined the order in which they received single doses of dexlansoprazole (n = 88) and esomeprazole (n = 87) for an ITT. Written informed consent was obtained from each patient. The patients were asked to complete the Chinese GERDQ upon recruitment. Blood samples were collected to measure the fasting blood sugar, serum cholesterol, and triglyceride levels. In addition, the BMI was calculated. A complete medical history and demographic data were obtained from each patient. The primary end points were the complete symptom resolution (CSR) rates at days 1, 3, and 7. CSR was defined as no reflux symptoms sufficient to impair the quality of life before the end of the initial treatment phase. The main outcome measures were the CSR rates at days 1, 3 and 7 of the initial treatment period. All patients starting esomeprazole or dexlansoprazole as their initial treatment were included in the ITT analysis. Patients with poor drug compliance were excluded from the PP analysis.
Thirteen patients were lost during the follow up period, resulting in the inclusion of 81 patients in each group in the PP analysis. The CSRs for both groups were similar at days 1, 3 and 7. In the subgroup analysis, 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 CSR was observed at day 7 (55.3% vs 36.8%, P = 0.09). 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). 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 conclusion of this study was that the overall CSR rates for GERD were similar on days 1 through 7 for both the dexlansoprazole and esomeprazole groups, although a higher incidence was observed on day 3 in female patients who received a single dose of dexlansoprazole. The findings of this study are novel, since no report has investigated the short-term clinical effects of dexlansoprazole 60 mg vs esomeprazole 40 mg. This comparison represents an unmet need for GERD treatment in real-world clinical practice. The findings in this study could have important implications for clinical practice in the future for the treatment of grade A and B GERD patients. Furthermore, this study observed that female sex was a negative predictive factor for CSR at post-dose days 1 and 3 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. The new theories proposed suggest that these observations could be due to differences in the pharmacokinetics of esomeprazole and dexlansoprazole. Esomeprazole is time- and dose-dependent, especially at days 1 and 5. No accumulation of dexlansoprazole occurs after multiple once-daily doses at 60 mg. The authors validated this possibility 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. In addition, there is ample evidence that estrogen and progestogen enhance relaxation of the lower esophageal sphincters and induce GERD symptoms, especially in post-menopausal women taking hormone replacement therapy. These hypotheses could 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.
The important message of this study is that rapid onset PPIs for fast symptom relief remains an unmet need for GERD treatment. However, no report has investigated the short-term clinical effects of dexlansoprazole 60 mg vs esomeprazole 40 mg. Thus, the findings of this pilot study are novel and may have important implications for clinical practice in the future for the treatment of patients with grades A and B GERD. This pilot study was hampered by the small sample size. We believe that large-scale randomized controlled trials are necessary to further fulfill the future perspectives.