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Examination on factors affecting symptom change after drug withdrawal in patients with erosive gastroesophageal re ux disease undergoing symptom-controlled maintenance therapy with acid- secretion inhibition drugs


 Background: In patients with gastroesophageal reflux disease (GERD) on maintenance therapy with acid-suppressive drugs, it is not clear what background factors allow patients to discontinue the drugs. The aim is to examine the relationship of the changes in the frequency and severity of gastrointestinal symptoms after discontinuation of acid-secretion inhibitors for erosive GERD (eGERD) with possible patient background factors, and to identify factors that influence these changes.Methods: This is a multicenter, open-label, interventional, exploratory study. eGERD patients with mild mucosal injury whose symptoms were under control and who were on maintenance therapy with acid-suppressive drugs were withdrawn from the drug treatment for 4 weeks. We examined the relationship of patient background (sex, age, body mass index, alcohol consumption, smoking habits), esophageal hiatal hernia, H. pylori infection, pepsinogen I and II concentrations and I/II ratios, blood gastrin levels before and after drug discontinuation with total score change in Frequency Scale for the symptoms of GERD (FSSG) .Results: Of the 92 patients whose symptoms could be assessed before and after drug withdrawal, 66 patients (71.7% of the total) had FSSG <8 and no symptom relapse after withdrawal. Furthermore, patient background factors that may be related to symptom relapse/non-relapse were examined, but no related factors were detected. The maintenance medications before discontinuation in the above 92 patients were a proton pump inhibitor (PPI) and vonoprazan (VPZ, a potassium ion competitive acid blocker). Since both drugs were administered to about the same number of patients though incidentally, we examined the relationship between patient background factors and symptom relapse/non-relapse by treatment group. As a result, no relevant background factors were detected in both groups. Although there were no significant differences between the two groups, the severity and frequency of symptom recurrence in the VPZ group tended to be higher than in the PPI group.Conclusions: Consideration of background factors is unlikely to be required in the discontinuation of maintenance therapy for eGERD. There was no significant difference in the extent of disease or frequency of recurrence during the discontinuation period, regardless of whether the drug before discontinuation was a PPI or VPZ.Trial registration: The study was registered in the UMIN Clinical Trial Registry (UMIN000029957).

Examination on factors affecting symptom change after drug withdrawal in patients with erosive gastroesophageal re ux disease undergoing symptom-controlled maintenance therapy with acidsecretion inhibition drugs Background Gastroesophageal re ux disease (GERD) is a disease with an extremely high recurrence rate and requires long-term management even the symptoms are mild [1,[2][3][4][5][6][7]. Proton pump inhibitors (PPIs) or vonoprazan (VPZ), a potassium-competitive acid blocker (P-CAB) with a stronger effect than PPIs, are the rst choice for medication of GERD in Japan [1]. The following clinical issues have been identi ed for PPIs: (1) the onset of effects takes several days after administration [8,9], (2) cytochrome P450s including CYP2C19 are involved in the metabolism resulting in individual differences due to genetic polymorphisms [10][11][12], (3) obtaining an inhibitory effect on acid secretion at night is di cult [13], and (4) PPIs are unstable under acidic conditions [14]. On the other hand, VPZ has been reported to almost overcome these issues [13][14][15][16][17], and was introduced in Japan in February 2015 [2].
When symptoms are once improved by the initial treatment with acid-secretion inhibition drugs (ASIDs), the maintenance, intermittent, on-demand, and step-down therapies are used to prevent recurrence by administering the lowest necessary dose of ASIDs in the subsequent long-term management and are recommended in the Japanese Guidelines for the Treatment of GERD 2015 [18], 2021 [1], and the US Guidelines [19]. The reasons for keeping acid suppression to the lowest necessary dose include avoiding the risk of side effects including neuroendocrine tumors [20][21][22][23] and Clostridioides di cile infection [24] associated with hypergastrinemia, which are concerns about long-term acid suppression, and costeffectiveness [25]. Rapid increase in gastric acid secretion is involved in the relapse of GERD symptoms after discontinuation of ASIDs, and it is reported that the larger the change in blood gastrin level before and after discontinuation, the more likely rebound occurs [26]. Thus, when considering the discontinuation of ASIDs in the maintenance treatment of GERD, it is important to maintain blood gastrin levels as low as possible before discontinuation and keep acid-suppressive therapy to the minimum necessary.
There are, however, questions about common factors in GERD patients who can discontinue ASIDs and about factors affecting the duration of discontinuation. Furthermore, there are no detailed reports on symptom recurrence after the discontinuation of maintenance therapy with VPZ.
In this study, we exploratively investigated factors associated with the change and incidence of symptoms after drug discontinuation in erosive GERD (eGERD) patients whose symptoms were controlled by maintenance therapy with ASIDs.  (3) patients whose symptoms had improved to a total score of <8

Subjects And Methods
in the subsequent retrospective questions on a patient self-completion questionnaire for the Frequency Scale for the Symptoms of GERD (FSSG).
The exclusion criteria were: subjects with severe mucosal injury of grade C/D in the LA classi cation, considering serious complications (bleeding and stenosis) associated with discontinuation of ASIDs.
Case setting: Based on a previous report [4], the incidence of symptoms after 4 weeks without treatment was assumed to be 40%. The number of target patients was set to 150 for which the 95% con dence interval of the incidence rate could be obtained with a precision of within ±10% (signi cance level 5% on both sides).
Methods: The treatment with ASIDs was stopped for the included patients. Based on a previous report [27], the observation period after discontinuation was set at 4 weeks.
Blood pepsinogen I and II levels including I/II ratio and blood H. pylori antibodies were measured at the time of withdrawal, and blood gastrin levels were measured at the initiation of withdrawal and Week 4 after withdrawal. The subjects were handed sheets of FSSG, Gastrointestinal Symptom Rating Scale (GSRS), and Hospital Anxiety and Depression Scale (HADS) at the withdrawal, and asked to complete the sheets at the initiation of withdrawal and Weeks 1, 2, 3, and 4. The symptom questionnaires were collected at the visit after Week 4. The survey items in the questionnaires and case reports are those described in Table 1 in addition to types/dosage of ASIDs, gastrointestinal drugs other than ASIDs, concomitant drugs, antiplatelet drugs excluding low-dose aspirin, anticoagulants, steroids, and bisphosphonates.
The intake of drugs including gastroprokinetic agents and antagonists of PPI, P-CAB, and H 2 -receptor affecting the study results were prohibited.
Evaluation and statistical analysis: We examined the association of the variation in FSSG total score with items given in Table 1 (primary endpoint).
Secondary endpoints were to examine the variations in the scores of GSRS, FSSG (re ux, dyskinesia), and HADS (depression) including subscales and factors affecting the variations.
Regarding the statistical methods employed, frequencies and percentages of background factors were presented as nominal and ordinal scales, and summary statistics were calculated for continuous quantities. Unpaired t-test and Fisher's exact probability test were performed according to the nature of the data. Each endpoint on Day 1 and at each measurement time point was analyzed using a paired ttest, while single regression analysis was used for the change in FSSG and GSRS scores. Hypothesis tests were two-tailed, and the signi cance level was set at 5% without considering multiplicity because the purpose was exploratory evaluation. SAS 9.4 (SAS Institute Inc., Cary, NC, USA) was used for all analyses.

Results
When setting up the study, the target number of enrolled patients was set at 150, but in reality, the planned number of patients was unable to be collected within the study period; thus, totaling 99 patients were enrolled. Of these, 93 subjects for whom FSSG scores on Day 1 were available were included in the analyses.
Patient background: Table 1 summarizes the summary statistics (mean ± SD) on Day 1 for the background factors and treatment factors that may affect eGERD treatment and shows the values for the entire patient population and for the respective PPI and VPZ groups, though the primary endpoint targeted the entire population only. Of the included 93 patients, male and female were respectively 55 (59.1%) and 38 (40.9%), without signi cant difference. Seventy subjects (75.3% of the total) were over 60 years of age. The drugs administered were either PPIs (esomeprazole: 27 cases, omeprazole: 1 case, rabeprazole: 15 cases, lansoprazole: 4 cases) or VPZ.
Although it was not initially set as an endpoint, since almost the same number of patients (N=45-47) were included in each PPI and VPZ group, we deviated from protocol to conduct inter-group comparison, and in Table 1 gives the data for the respective groups. The results show that there were statistically signi cant inter-group differences (p<0.05) for sex, BMI, blood gastrin levels, blood pepsinogen I, II levels, I/II ratios, and LA classi cation A/B, but no inter-group differences in other parameters.
Symptom relapse after drug withdrawal, non-relapse factors, and change in blood gastrin level: Mean±SD of summary statistics at Week 4 for the same items as in Table 1 is shown for entire population and the patients strati ed by FSSG < 8 (non-relapse) and FSSG≥ 8 (relapse) ( Table 2).
Although symptoms of 92 patients could be assessed just before and after the withdrawal, since there were some subjects missing some data for the items on Day 1 or Week 4, the evaluation of variations could be performed in 91 cases. Of the 91 patients, 66 (72.5%) had FSSG <8 after withdrawal.
There was no statistically signi cant difference (p<0.05) between the patients with FSSG< 8 and FSSG≥ 8 in any of the items examined, and there was no association of symptom relapse with any of the factors. Table 3 shows the respective blood gastrin levels and variations from Day 1 to Week 4 for entire population and each group. The amount of variation was signi cantly lower at Week 4. Since there was already a signi cant inter-group difference on Day 1, we performed a covariance analysis using the Day 1 values as covariates; the inter-group difference was statistically insigni cant at p=0.808 (Table 4).
Symptom transition after drug suspension: Table 5 shows the FSSG total scores at Day 1 and each Week for entire population and the patients in the two groups. The total scores at each Week were higher than those on Day 1 with statistical signi cance (p<0.001) in the two dose groups and entire population. Comparison of the two groups for the variations in FSSG total scores at each time point (unpaired t-test) demonstrates that the VPZ group was higher than the PPI group, though without statistical signi cance (Fig. 1). The results of the subscores by acid re ux-related symptom and motor de ciency symptom are shown in Tables 6 and 7, respectively. The comparison of the amount of variation in the FSSG subscores at each time point shows an increasing trend over time without signi cant difference, and the comparison of the two groups (unpaired t-test) shows no signi cant difference. However, all the subscores were higher in the VPZ group than those in the PPI group at each time point (Figs 2 and 3).
Next, we examined the GSRS total scores/subscores and the HADS scores; between Day 1 and each time point, there was no signi cant difference in the amount of variations in the HADS scores but the difference in the GSRS total score was signi cant at p<0.001. There were also signi cant differences in the subscales of acid re ux and abdominal pain. Indigestion, diarrhea, and constipation, however, show no signi cant difference (See Table 1 in Supplementary le).
The percentage of subjects with FSSG total score of ≥8 in the two groups and entire population was calculated using the number of subjects on Day 1 as the denominator (Fig. 4). To assess whether the distribution of FSSG total score (<8/≥8) at each time point differed among the ASIDs, we compared it by Fisher's exact probability test. As a result, no statistically signi cant difference was obtained at any time points. The number of subjects in the VPZ group with FSSG total score of ≥8, however, remained around 30% except for 39.1% at Week 3. In the PPI group, the number of subjects with FSSG total score of ≥8 showed an upward tendency over time from approximately 15% to 21% except for 27.7% at Week 4.
A single regression analysis was performed with the amount of variations in FSSG total scores at Week 4 as the objective variable and the background factors of continuous volume (age, BMI, blood gastrin levels, and pepsinogen I/II ratios at enrollment) and questionnaire results at the enrollment (total scores of FSSG, GSRS, and HADS) as explanatory variables. No statistically signi cant correlations were observed for any of the factors, and for the FSSG subscores. Single regression analysis of the variations in GSRS subscores at Week 4 shows weak correlations with BMI of 0.2562 for the acid re ux subscore, Day 1 blood gastrin level of 0.2081 for abdominal pain, and age of 0.2874 for the constipation score (See Table 2 of Supplementary le).

Discussion
The above results demonstrate that we could suspend the ASIDs for at least 4 weeks in nearly 70% of eGERD patients with mild mucosal injury under control on maintenance therapy with ASIDs.
The primary endpoint of this study was to examine patient background factors affecting drug withdrawal in the entire patient population, but we could not identify such factors in practice. Each patient received either PPIs or VPZ, and approximately equal numbers of patients (n=45-47) were incidentally distributed in the PPI and VPZ groups (Table 1). Therefore, we tried to compare the two groups, although this was not an endpoint set in the protocol. Among the patient backgrounds, statistically signi cant inter-group differences (p<0.05) were observed for sex, BMI, blood gastrin levels, blood pepsinogen I and II concentrations and I/II ratios, and LA classi cation A /B. The higher blood gastrin levels in the VPZ group may be attributable to the higher inhibitory effect of VPZ on acid secretion than PPIs. Similar results are reported in several papers [28][29][30]. The reason why blood pepsinogen I/II concentrations were higher in the VPZ-treated group may be attributable to the high acid-secretion inhibition effect of VPZ.
It is interesting to note that blood gastrin levels (Table 1), FSSG total scores (Table 5), and FSSG subscores (Tables 6, 7) were tended to be higher in the VPZ group than those in the PPI group on Day 1 and Week 4.
The following factors, which are likely to affect symptoms after the drug withdrawal, were examined: patient background items listed in Table 1; total score and subscores of FSSG, HADS, and GSRS; and other gastrointestinal drugs and concomitant medications in use. No correlative factors were found except for BMI exhibiting a weak correlation with the acid-re ux related GSRS subscore, and age exhibiting a weak correlation with the constipation score. The FSSG was additionally strati ed into ≥8 and <8 to examine factors correlated with disease status, but no correlative factors were found ( Table 2).
This result may be attributable to the smaller number of patients, but there is possibility that the factors examined do not have a strong association with GERD relapse during withdrawal. Thus, patients with certain backgrounds are not more prone to relapse; suggesting that there is little need to take the patient backgrounds into account in drug discontinuation.
There was no statistically signi cant inter-group difference in symptom recurrence after drug withdrawal, but there was a tendency toward a higher frequency of recurrence in the VPZ group at each week. In the VPZ group, the FSSG total score of ≥8 was around 30% at each time point, whereas in the PPI group it was from 15% to 21% (Fig. 4). This tendency toward a high relapse incidence in the VPZ group is consistent with the greater change in blood gastrin levels in this group.
The review by the American Gastroenterological Association [31] describes that PPIs have little causality with adverse events including renal impairment, dementia. We previously reported that the effect of VPZ is considerably stronger than the rabeprazole belonging to PPIs; VPZ maintained a high pH even at doses as low as 1/2-1/4 times the standard dose of rabeprazole. Therefore, VPZ caused signi cantly higher blood gastrin levels. This is consistent with the result that VPZ had shorter blood half-life of 7.7 hr than that in the stomach where VPZ remains as unchanged drug for a longer time because it was inactivated by acid [32]. There are no reports on serious side effects of VPZ for up to two years [33], but elucidation of the safety of VPZ in long-term maintenance therapy is important. This study show that there was no signi cant inter-group difference (p<0.05) in most of the patient background factors on Day 1, except for blood gastrin level, pepsinogen levels and I/II ratios, and LA classi cation. Among these, blood gastrin levels were signi cantly higher in the VPZ group (383.3±281.7 pg/mL) than those in the PPI group (800.3±603.5 pg/mL: the nding being consistent with the description in the above report [30].
There is a report [34] a rming the acid hypersecretion by ASID discontinuation, but several articles [35][36][37] reporting that this is not a major problem. We have, however, thought that the possibility of acid hypersecretion is important in discontinuation of drugs with strong e cacy.
If the goal is to wean patients from ASID in the treatment of GERD, it is important to keep in mind the side effects that may occur during the maintenance therapy and the need to avoid rebound after discontinuation. From these points of view, the maintenance therapy for GERD should avoid unnecessarily prolonged strong acid-secretion suppression, even if symptoms are improving.
There are several limitations to this study: (1) the number of subjects was smaller than originally planned, (2) the drug withdrawal period was 4 weeks, and (3) endoscopy was not performed after the drug withdrawal.

Conclusion
There were no patient factors to be considered in the discontinuation of maintenance therapy for eGERD. There was no signi cant difference in the extent of disease or frequency of recurrence during the discontinuation period, regardless of whether the drug before discontinuation was PPIs or VPZ. Since 70% of patients did not experience recurrence for at least 4 weeks and there were no serious complications even in patients experiencing recurrence, temporary discontinuation of maintenance therapy with ASIDs, especially with PPIs, is acceptable for mild eGERD.

Abbreviations Abbreviation
Meaning of abbreviation Availability of data and materials The datasets during and/or analyzed during this study are available from the corresponding author on reasonable request.

Competing interests
All authors declare that they have no competing interests.

Funding
This research was nancially supported with an Investigator Sponsored Study Program of AstraZeneca Co. Ltd., Japan.

Authors' contributions
Takeuchi T: Preparation, reviewing, and edition of this paper, performing data curation and formal analysis, and supervising methodology and visualization. Tanaka           Change of variation of FSSG total score from Day 1 Figure 2 Change of variation of FSSG sub-score related to acid re ux from Day 1 Figure 3 Change of variation of FSSG sub-score related to dysmotility from Day 1 Page 24/24

Figure 4
Percentage of patients showing FSSG total score of 8 or higher at each time point

Supplementary Files
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