The safety of long-term proton pump inhibitor (PPI) and vonoprazan (VPZ) use is a relatively recent concern. Gastric mucosal redness was reported as a VPZ-associated lesion in a previous study. The aim of this study was to investigate the prevalence and risk factors for gastric mucosal redness. Between December 2020 and November 2021, 1,101 patients who underwent esophagogastroduodenoscopy were reviewed. The cohort was divided into four groups: Control (n=580), histamine-2 receptor antagonist (H2RA) (n=65), PPI (n=146) and VPZ groups (n=310). Gastric mucosal redness was present in 48/1,101 patients (4%). The prevalence in controls, H2RA, PPI and VPZ groups was 1.9% (11/580), 1.5% (1/65), 6.2% (9/146) and 8.7% (27/310), respectively. Both the PPI and VPZ groups had a significantly higher prevalence of gastric mucosal redness compared with the control group (P<0.001). In the multivariate analysis, PPI and VPZ use were significantly associated with gastric mucosal redness. Fundic gland polyps, gastric hyperplastic polyps, multiple white and flat elevated lesions, cobblestone-like mucosa, and stardust gastric mucosa were also significantly associated with PPI and VPZ use in the multivariate analysis. Back-to-back analysis showed that gastric mucosal redness was not seen before starting PPI/VPZ in most patients. The duration of treatment with VPZ was investigated to determine if it affected the prevalence of gastric mucosal redness. There were no significant differences in treatment duration among patients with and without gastric mucosal redness (mean ± standard deviation: 3.0±1.5 vs. 2.5±1.4 years, P=0.077). In conclusion, the prevalence of gastric mucosal redness was low but was associated with PPI and VPZ use.
The long-term safety of acid blockers is a relatively recent concern for general practitioners as well as gastroenterologists. Vonoprazan (VPZ), a potassium-competitive acid blocker, was made available in 2015 and has a stronger acid-suppressing effect than proton pump inhibitors (PPI) (
In 2020, Kubo
This study was a retrospective observational study based on the medical records and endoscopic reports of patients who underwent esophagogastroduodenoscopy (EGD). Patients who underwent EGD at the Shinozaki Medical Clinic (Utsunomiya, Tochigi, Japan) between December 2020 and November 2021 were included. The medications taken by each patient were verified before EGD by checking the personal ‘medicine notebook’ issued by the Japan Pharmaceutical Association and scrupulously maintained by each patient that documents all prescriptions regardless of the medical facility that prescribed it. When multiple EGDs were performed on one patient during the study period, only the first EGD was included. At least 1-year of continuous administration of VPZ, PPI, and H2RA was confirmed using the medicine notebook. Patients with current
All EGDs were performed by the first author and recorded on video. In the case of unclear findings or lack of data, the video was immediately checked. An ultrathin endoscope (EG-L580NW7, Fujifilm Corporation) was used and endoscopic observation was performed using linked color imaging throughout the procedure (
The frequency of gastric mucosal changes was compared among the four groups in this study using a χ2 test. Univariate analysis was performed using a logistic regression model. To diminish the influence of confounding factors, multivariate logistic regression analysis was used. Factors for multivariate analysis were selected based on clinical significance. To compare continuous data between two groups, a Student's t-test was used. Statflex version 7.0 software (Artech Co. Ltd.) was used for all statistical analyses. P<0.05 was considered to indicate a statistically significant difference.
Almost half of the patients (47%) were treated with acid blockers (
The 1,101 included patients were divided into four groups: Controls, H2RA, PPI, and VPZ groups (
Additionally, the prevalence of five representative changes associated with acid blockers including fundic gland polyps, gastric hyperplastic polyps, multiple white and flat elevated lesions, cobblestone-like mucosa, and stardust gastric mucosa were compared (
Risk factors for gastric mucosal redness were investigated (
We previously reported four representative gastric mucosal changes associated with acid blocker use (
Among the 48 patients who had gastric mucosal redness, 9 and 27 patients were undergoing PPI and VPZ therapy, respectively. EGD data existed for 7/9 patients in the PPI group and in 26/27 patients in the VPZ group [naïve (n=15) and changed from PPI (n=11)] before starting their respective therapy. EGD data were reviewed to determine the presence or absence of gastric mucosal redness before starting PPI or VPZ to perform back-to-back analyses (
The duration of treatment with VPZ was investigated to determine if it affected the prevalence of gastric mucosal redness. The mean VPZ treatment duration was 2.6 years (n=310). There were no significant differences in treatment duration among patients with and without gastric mucosal redness (mean ± standard deviation: 3.0±1.5 vs. 2.5±1.4 years, P=0.077). The treatment duration with VPZ did not affect the prevalence of gastric mucosal redness. Regarding the H2RA and PPI groups, formal evaluation could not be performed due to the lack of a sufficient number of patients in these groups.
The present study demonstrated the influence of acid blockers on the prevalence of gastric mucosal redness. The overall prevalence of gastric mucosal redness is low (4%), even in patients treated with PPI or VPZ (6-9%). Both PPI and VPZ use were identified as significant factors contributing to the development of gastric mucosal redness. Most instances of gastric mucosal redness occurred after starting PPI or VPZ. Treatment duration with VPZ was not associated with the prevalence of gastric mucosal redness. To the best of our knowledge, this is the first study reporting the prevalence and risk factors for the development of gastric mucosal redness.
Few studies are available regarding the development of gastric mucosal redness secondary to the use of acid blockers and its pathogenesis is unknown (
Estimation of the malignant potential of gastric mucosal redness is important. According to previous reports, gastric mucosal redness disappears after cessation of VPZ (
In the multivariate analysis, the VPZ group had a slightly stronger association with the development of gastric mucosal redness compared to the PPI group. The degree of acid inhibition may contribute to the prevalence of gastric mucosal redness. A case series reported ‘VPZ-associated gastric mucosal redness’ and changing therapy to PPI results in the disappearance of the lesion (
The treatment duration with VPZ in the present study (median: 2.6 years) was long, and patients treated with acid blockers for <1 year were excluded. Treatment duration with VPZ was not associated with the prevalence of gastric mucosal redness. Past case series reported that gastric mucosal redness presented 2-6 months after starting VPZ (
There are some limitations to this study. First, this is a retrospective observational study, but gastric mucosal redness was managed as a compulsory item in the endoscopic report and all EGD procedures were recorded on video. Second, the data after cessation of PPI/VPZ were not assessed. It is hypothesized that the development of gastric mucosal redness does not necessitate cessation of PPI/VPZ unless it is considered to be a source of hemorrhage. This mucosal finding may be a phenotype of persistent inflammatory changes and increased intramucosal blood flow with hyperplastic glands, but not neoplastic changes. Third, the diagnosis of gastric mucosal redness was determined only based on endoscopic findings without pathological evaluation. Gastric mucosal redness may be similar to diffuse redness caused by a current
In conclusion, the prevalence of gastric mucosal redness was low. Gastric mucosal redness is associated with PPI use as well as VPZ use and is not influenced by the treatment duration with VPZ. Due to the inflammatory nature of this lesion, the presence of gastric mucosal redness does not necessitate the cessation of acid blocker therapy. To the best of our knowledge, this is the first original report investigating the influence of PPI or VPZ on gastric mucosal redness.
Not applicable.
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
SS and HO conceived and designed the study, collected, analyzed and interpretated the data, and drafted the manuscript. YM, HY, HS were involved in conception and design of the study, and in the drafting of the manuscript. TY was involved in conception and design of the study, drafting of the manuscript, and in the data analysis and interpretation. AKL and HY were involved in the drafting of the manuscript, and in data analysis and interpretation. SS and HO confirm the authenticity of all the raw data. All authors have read and reviewed the final manuscript.
The present study was approved by the Institutional Review Board of the Shinozaki Medical Clinic (approval no. ID#31-R001). The need for written informed consent was waived due to the retrospective design of the study.
Not applicable.
SS has received honoraria from Takeda and Otsuka Pharmaceuticals. HO has received honoraria from AstraZeneca, Daiichi Sankyo, Takeda and Otsuka Pharmaceuticals. YM has received honoraria from AstraZeneca, Daiichi Sankyo, Takeda, Otsuka and EA Pharmaceuticals. HY has received honoraria from Takeda Pharmaceutical. All other authors declare no conflicts of interest regarding this study.
Endoscopic images of gastric mucosal redness using linked color imaging. (A) Distant view of spotty and linear areas of redness along the greater curvature of the upper body and fundus of the stomach in a patient undergoing vonoprazan therapy; (B) near view showing multiple small round pits surrounded by redness on bump-like mucosa.
Microscopic images of areas of gastric mucosal redness. (A) Slight lymphatic infiltration and dilated oxyntic glands (magnification, x100); (B) high power field within the blue box. Increased numbers of parietal cells are evident with protrusion. Congestion and dilated vessels underneath the surface epithelium (magnification, x200).
The prevalence of gastric mucosal redness in each group. All differences among groups were evaluated, but only statistically significant results are described. H2RA, histamine-2 receptor antagonist; PPI, proton pump inhibitor, VPZ, vonoprazan.
The prevalence of five representative gastric lesions associated with acid blockers in each group. (A) Fundic gland polyps, (B) gastric hyperplastic polyps, (C) multiple white and flat elevated lesions, (D) cobblestone-like mucosa and (E) stardust gastric mucosa. All differences among groups were evaluated, but only statistically significant results are described. H2RA, histamine-2 receptor antagonist; PPI, proton pump inhibitor; VPZ, vonoprazan.
Presence or absence of gastric mucosal redness before initiation of PPI or VPZ therapy (A) PPI group; (B) VPZ group (naïve); (C) VPZ group (changed from PPI). PPI, proton pump inhibitor; VPZ, vonoprazan.
Baseline characteristics and endoscopic findings of the recruited cohort.
Characteristic | Value |
---|---|
Age, years, mean ± standard deviation | 62.9±14.8 |
Sex, n (%) | |
Male | 492 (45%) |
Female | 609 (55%) |
Acid suppression drug, n (%) | |
None | 580 (53%) |
Histamine-2 receptor antagonist | 65 (6%) |
Proton pump inhibitor | 146 (13%) |
Vonoprazan | 310 (28%) |
Degree of gastric atrophy, n (%) | |
None | 470 (43%) |
Closed type | 296 (27%) |
Open type | 335 (30%) |
Fundic gland polyps, n (%) | 366 (33%) |
Gastric hyperplastic polyps, n (%) | 48 (4%) |
Multiple white and flat elevated lesions, n (%) | 235 (21%) |
Cobblestone-like mucosa, n (%) | 52 (5%) |
Stardust gastric mucosa, n (%) | 168 (15%) |
Gastric mucosal redness, n (%) | 48 (4%) |
Factors associated with gastric mucosal redness.
Univariate analysis | Multivariate analysis | |||||
---|---|---|---|---|---|---|
Factor | Odds ratio | 95% confidence interval | P-value | Odds ratio | 95% confidence interval | P-value |
Age ≥60 y | 2.102 | 1.035-4.266 | 0.039 |
1.327 | 0.616-2.861 | 0.470 |
Male sex | 1.146 | 0.642-2.044 | 0.645 | |||
Histamine-2 receptor antagonist use | 0.329 | 0.045-2.422 | 0.274 | |||
Proton pump inhibitor use | 1.530 | 0.725-3.228 | 0.264 | 2.665 | 1.061-6.692 | 0.036 |
Vonoprazan use | 3.498 | 1.946-6.288 | <0.001 |
3.415 | 1.477-7.899 | 0.004 |
Open type gastric atrophy | 1.673 | 0.929-3.015 | 0.086 | 1.553 | 0.825-2.924 | 0.172 |
Fundic gland polyps | 1.596 | 0.890-2.864 | 0.116 | |||
Gastric hyperplastic polyps | 4.214 | 1.783-9.961 | 0.001 |
2.384 | 0.975-5.828 | 0.056 |
Multiple white and flat elevated lesions | 0.968 | 0.475-1.974 | 0.929 | |||
Cobblestone-like mucosa | 1.903 | 0.657-5.514 | 0.235 | |||
Stardust gastric mucosa | 3.612 | 1.964-6.643 | <0.001 |
1.650 | 0.781-3.485 | 0.189 |
aP≤0.05,
bP≤0.01,
cP<0.001.
Factors associated with fundic gland polyps.
Univariate analysis | Multivariate analysis | |||||
---|---|---|---|---|---|---|
Factor | Odds ratio | 95% confidence interval | P-value | Odds ratio | 95% confidence interval | P-value |
Age ≥60 y | 0.807 | 0.622-1.048 | 0.107 | |||
Male sex | 0.598 | 0.462-0.773 | <0.001 |
0.669 | 0.498-0.898 | 0.007 |
Histamine-2 receptor antagonist use | 1.029 | 0.606-1.748 | 0.915 | 2.161 | 1.169-3.995 | 0.013 |
Proton pump inhibitor use | 2.976 | 2.089-4.240 | <0.001 |
5.932 | 3.744-9.401 | <0.001 |
Vonoprazan use | 1.800 | 1.371-2.362 | <0.001 |
2.817 | 2.019-3.931 | <0.001 |
Open type gastric atrophy | 0.086 | 0.055-0.136 | <0.001 |
0.069 | 0.043-0.112 | <0.001 |
Gastric mucosal redness | 1.596 | 0.890-2.864 | 0.116 | |||
Gastric hyperplastic polyps | 1.460 | 0.811-2.628 | 0.207 | |||
Multiple white and flat elevated lesions | 1.749 | 1.301-2.351 | <0.001 |
1.389 | 0.965-1.999 | 0.077 |
Cobblestone-like mucosa | 2.085 | 1.193-3.646 | 0.009 |
|||
Stardust gastric mucosa | 1.449 | 1.034-2030 | 0.031 |
aP≤0.05,
bP≤0.01,
cP<0.001.
Factors associated with gastric hyperplastic polyps.
Univariate analysis | Multivariate analysis | |||||
---|---|---|---|---|---|---|
Factor | Odds ratio | 95% confidence interval | P-value | Odds ratio | 95% confidence interval | P-value |
Age ≥60 y | 2.788 | 1.292-6.019 | 0.009 |
|||
Male sex | 0.879 | 0.489-1.581 | 0.667 | |||
Histamine-2 receptor antagonist use |
||||||
Proton pump inhibitor use | 3.894 | 2.096-7.233 | <0.001 |
15.886 | 5.742-43.952 | <0.001 |
Vonoprazan use | 3.200 | 1.785-5.737 | <0.001 |
10.725 | 4.050-28.402 | <0.001 |
Open type gastric atrophy | 1.393 | 0.765-2.536 | 0.278 | |||
Gastric mucosal redness | 4.214 | 1.783-9.961 | 0.001 |
2.551 | 1.050-6.194 | 0.038 |
Fundic gland polyps | 1.460 | 0.811-2.628 | 0.207 | |||
Multiple white and flat elevated lesions | 1.100 | 0.552-2.192 | 0.785 | |||
Cobblestone-like mucosa | 2.489 | 0.942-6.573 | 0.065 | |||
Stardust gastric mucosa | 2.964 | 1.588-5.533 | <0.001 |
aP≤0.05,
bP≤0.01,
cP<0.001.
dNo gastric hyperplastic polyp in the histamine-2 receptor antagonist group.
Factors associated with multiple white and flat elevated lesions.
Univariate analysis | Multivariate analysis | |||||
---|---|---|---|---|---|---|
Factor | Odds ratio | 95% confidence interval | P-value | Odds ratio | 95% confidence interval | P-value |
Age ≥60 y | 3.466 | 2.387-5.033 | <0.001 |
2.767 | 1.869-4.096 | <0.001 |
Male sex | 0.481 | 0.354-0.653 | <0.001 |
0.507 | 0.365-0.704 | <0.001 |
Histamine-2 receptor antagonist use | 0.655 | 0.329-1.306 | 0.229 | |||
Proton pump inhibitor use | 2.964 | 2.051-4.283 | <0.001 |
3.070 | 1.962-4.804 | <0.001 |
Vonoprazan use | 1.959 | 1.446-2.653 | <0.001 |
1.768 | 1.140-2.741 | 0.010 |
Open type gastric atrophy | 1.237 | 0.910-1.681 | 0.174 | |||
Gastric mucosal redness | 0.968 | 0.475-1.974 | 0.929 | |||
Fundic gland polyps | 1.749 | 1.301-2.351 | <0.001 |
1.361 | 0.978-1.893 | 0.067 |
Gastric hyperplastic polyps | 1.100 | 0.552-2.192 | 0.785 | 0.542 | 0.262-1.122 | 0.098 |
Cobblestone-like mucosa | 3.131 | 1.775-5.524 | <0.001 |
2.036 | 1.093-3.793 | 0.025 |
Stardust gastric mucosa | 2.832 | 1.992-4.028 | <0.001 |
1.846 | 1.167-2.920 | 0.008 |
aP≤0.05,
bP≤0.01,
cP<0.001.
Factors associated with cobblestone-like mucosa.
Univariate analysis | Multivariate analysis | |||||
---|---|---|---|---|---|---|
Factor | Odds ratio | 95% confidence interval | P-value | Odds ratio | 95% confidence interval | P-value |
Age ≥60 y | 2.669 | 1.287-5.536 | 0.008 |
|||
Male sex | 1.596 | 0.911-2.796 | 0.102 | 1.955 | 1.084-3.526 | 0.025 |
Histamine-2 receptor antagonist use | 0.626 | 0.149-2.632 | 0.522 | 4.778 | 0.855-26.714 | 0.074 |
Proton pump inhibitor use | 3.776 | 2.072-6.882 | <0.001 |
16.826 | 5.500-51.473 | <0.001 |
Vonoprazan use | 3.173 | 1.809-5.567 | <0.001 |
12.683 | 4.367-36.833 | <0.001 |
Open type gastric atrophy | 1.017 | 0.556-1.860 | 0.956 | |||
Gastric mucosal redness | 1.903 | 0.657-5.514 | 0.235 | |||
Fundic gland polyps | 2.085 | 1.193-3.646 | 0.009 |
|||
Gastric hyperplastic polyps | 2.489 | 0.942-6.573 | 0.065 | |||
Multiple white and flat elevated lesions | 3.131 | 1.775-5.524 | <0.001 |
2.107 | 1.151-3.856 | 0.015 |
Stardust gastric mucosa | 2.141 | 1.133-4.045 | 0.019 |
aP≤0.05,
bP≤0.01,
cP<0.001.
Factors associated with stardust gastric mucosa.
Univariate analysis | Multivariate analysis | |||||
---|---|---|---|---|---|---|
Factor | Odds ratio | 95% confidence interval | P-value | Odds ratio | 95% confidence interval | P-value |
Age ≥60 y | 2.026 | 1.378-2.977 | <0.001 |
|||
Male sex | 0.684 | 0.488-0.960 | 0.028 |
0.613 | 0.401-0.937 | 0.023 |
Histamine-2 receptor antagonist use |
||||||
Proton pump inhibitor use | 0.664 | 0.373-1.114 | 0.115 | 23.192 | 6.553-82.080 | <0.001 |
Vonoprazan use | 37.603 | 22.654-62.417 | <0.001 |
192.686 | 60.197-616.771 | <0.001 |
Open type gastric atrophy | 1.099 | 0.772-1.564 | 0.599 | |||
Gastric mucosal redness | 3.612 | 1.964-6.643 | <0.001 |
2.032 | 0.957-4.315 | 0.064 |
Fundic gland polyps | 1.449 | 1.034-2.030 | 0.031 |
0.714 | 0.468-1.088 | 0.116 |
Gastric hyperplastic polyps | 2.964 | 1.588-5.533 | <0.001 |
|||
Multiple white and flat elevated lesions | 2.832 | 1.992-4.028 | <0.001 |
1.930 | 1.229-3.031 | 0.004 |
Cobblestone-like mucosa | 2.141 | 1.133-4.045 | 0.019 |
aP≤0.05,
bP≤0.01,
cP<0.001.
dNo gastric hyperplastic polyp in the histamine-2 receptor antagonist group.