Effects of vonoprazan on gastric PH and clinical course after gastric ESD: A retrospective and prospective study

Background Vonoprazan has been more widely used for artificial ulcers after endoscopic submucosal dissection (ESD) for early gastric cancer; however, no reports have examined intragastric pH during ESD. The present study aimed to measure gastric pH at the time of ESD and the clinical course afterwards for patients treated with vonoprazan the night before undergoing ESD. Materials and methods We examined medication status regarding gastric acid secretion and antithrombotic drugs, post-ESD bleeding as a perioperative complication, and the timing of upper gastrointestinal endoscopy after ESD and ulcer healing in 156 patients who underwent gastric ESD at our hospital from January 2014 to December 2019. The gastric pH was measured at the time of ESD after administration of 20 mg vonoprazan on the night before gastric ESD. Results There were 14 cases of post-ESD bleeding in patients treated with proton-pump inhibitors (PPIs), including oozing during second-look endoscopy compared to only 1 case of bleeding with vonoprazan administration (p < 0.05). Vonoprazan was also associated with better post-ESD ulcer healing than PPIs. Gastric pH during ESD after vonoprazan administration on the night before gastric ESD was ≥6.96 in all 11 patients. Conclusion Post-ESD bleeding was reduced, and ulcer healing was improved in patients treated with vonoprazan the night before their procedure. Our results suggest high gastric pH during ESD due to vonoprazan administration may be beneficial for hemostasis and ulcer healing following ESD.


Introduction
Several studies have reported on the effects of vonoprazan on postendoscopic submucosal dissection (ESD) ulcers; however, none have reported the effects of gastric pH during ESD. It takes several days for the gastric pH to reach a high level with conventional gastric acid secretion inhibitors, such as proton-pump inhibitors (PPIs) [1]. Vonoprazan, a potassium-competitive acid blocker [2] that has been available since February 2015, is highly basic, accumulates in the secretory tubules of parietal cells for a long time [3], and is more potent than PPIs [4]. Gastric pH reportedly rises to ≥4 within 4 h after vonoprazan administration [3,5]. ESD is performed as an endoscopic treatment for early gastric cancer; however, the incidence of bleeding or perforation from an artificial ulcer after ESD has been reported as approximately 3.5% [6][7][8][9][10].
PPI administration after ESD suppresses gastric acid secretion and improves post-ESD ulcer healing, especially because gastric acid is involved in the development of post-ESD bleeding [11][12][13]. However, even if PPIs are administered after ESD, there is a risk of bleeding because PPIs cannot adequately increase gastric pH on the day of or day after ESD [3,5]. Therefore, second-look endoscopy and clinical findings on the day after ESD are important. Vonoprazan has been reported to increase intragastric pH immediately after oral administration [3,5]; therefore, its administration on the day before ESD should increase intragastric pH during ESD and may thereby reduce the risk of bleeding. Vonoprazan is now popular for treating artificial ulcers occurring after ESD performed for early gastric cancer and is superior to PPIs in preventing post-ESD bleeding [14,15] and promoting ulcer healing [16,17]. Although gastric pH is considered important for ulcer healing and preventing upper gastrointestinal bleeding, the effects of vonoprazan administration on gastric pH at the time of ESD have not been reported. In our hospital, a second-look endoscopy is often performed the day after ESD. Therefore, the present study aimed to examine the actual clinical course (including findings from the second-look endoscopy coupled with the clinical assessment) and measure gastric pH at the time of ESD after vonoprazan administration on the night before gastric ESD.

Retrospective clinical course analysis
From January 2014 to December 2019, 156 patients (115 men and 41 women) who underwent gastric ESD at our hospital were enrolled. Post-ESD course and upper gastrointestinal endoscopy findings were examined from clinical records. The work has been reported in line with the STROCSS criteria [18].

Prospective analysis of intragastric pH
Of the 19 patients who underwent gastric ESD between June 2019 and March 2020, we excluded 5 patients who were taking acid secretion inhibitors, 1 patient who did not provide informed consent, and 2 patients who had no gastric juice in their stomachs. Finally, 11 patients (7 men and 4 women) were included in the present study. Patients were administered 20 mg vonoprazan on the night before gastric ESD. The gastric juice was collected immediately after endoscope insertion in the stomach. The pH meter 206-pH5 (Tesuto co., Kanagawa, Japan) was used. Statistical analysis was performed through the chi-square test using js-STAR version 9.8.3j (http://www.kisnet.or. jp/nappa/software/star/freq/chisq_ixj.htm#).

Retrospective clinical course analysis
The patients had an average age of 70.7 (45-90) years. Gastric lesions were present in 31 U regions, 68 M regions, and 57 L regions, according to the Japanese classification of gastric cancer [19] (Table 1). Clinical bleeding occurred in 5 patients (3.2%), and minor oozing and bleeding during the second-look endoscopy were noted in 10 patients (6.4%) (  (Table 3).
Five (3.2%) of the 156 patients experienced clinically problematic bleeding. Of the 90 patients who underwent second-look endoscopy, 10 (11.1%) had minor bleeding during the endoscopy: 8 had minor oozing, and 2 had bleeding ( Table 2). PPIs were administered in 14 of 15 patients with bleeding, while only 1 patient was administered vonoprazan (Table 3), who was gastrectomized and experienced bleeding in the residual stomach (Table 4). The bleeding ratio was significantly lower in vonoprazan administered patients. The incidence of bleeding (major and minor) was 13.8% (14/

Prospective analysis on intragastric pH
The average gastric pH was 7.68 ± 0.62 ( Table 6). The gastric pH was ≥6.96 in all 11 patients, regardless of the tumor location, histological type, and sex.

Discussion
The present study showed that gastric pH was adequately high under vonoprazan 20 mg administration on the night before gastric ESD, which may be beneficial for hemostasis and healing of ulcers following ESD. When the gastric pH is below 5.4, neither platelet aggregation nor plasma coagulation occurs [20]. Because blood coagulation and platelet aggregation are pH-dependent [13], suppression of gastric acid is important for the prevention of gastric bleeding [21][22][23].
A high intragastric pH at the time of ESD would be advantageous for hemostasis during surgery and prevention of bleeding immediately after ESD. In this study, 14 of 101 PPI-administered patients (13.8%) experienced bleeding compared to only 1 (2%) of 55 vonoprazanadministered patients, including subclinical bleeding cases during second-look endoscopy.
Previous reports have shown that ordinal PPIs delay sustained gastric acid secretion [25]; however, vonoprazan can reach steady-state acid levels early after intake [1]. Most studies report that vonoprazan is better at healing ulcers than PPIs. Tsuchiya et al. [16] and Maruoka et al. [17] reported that the rate of ulcer scarring after ESD was significantly higher with vonoprazan than with esomeprazole. Vonoprazan is a potent gastric acid secretion inhibitor and effective in healing ulcers after gastric ESD. However, Miwa et al. [26] and Takahashi et al. [27] reported that ulcer healing after ESD was not significantly different between vonoprazan and PPI. This difference in the results has been  attributed to the different sizes of the ulcers after ESD and the number and background of the cases. In our study, only one vonoprazan-administered patient (1/32, 3%) did not have ulcer scarring during upper gastrointestinal endoscopy performed about 8 weeks after ESD. In contrast, 11 PPI-administered patients (11/64, 17%) had open ulcers. The scarring ratio was significantly higher in the vonoprazan administered patients. Limitations of this study include it being conducted a single-center study with relatively small sample size; however, it is thought that increasing stomach pH early by vonoprazan administration will have an advantageous effect on ulcer healing. Thus, vonoprazan administration on the day before ESD may contribute to the suppression of bleeding during and after ESD. Preoperative administration of vonoprazan before the ESD may reduce the risk of bleeding and make post-ESD management even more comfortable.

Conclusions
Our study showed that gastric pH is adequately high after vonoprazan administration on the day before ESD, which presumably facilitates hemostasis and healing of ulcers following ESD. With preoperative vonoprazan administration, post-ESD bleeding was less frequent, and post-ESD ulcer healing was better.

Ethical approval
The study was approved by the Ethics Committee of International University of Health and Welfare Hospital [approval number: 13-B-355]. The study participants have given oral and written consent.

Sources of funding
None to declare.

Author contribution
All authors contributed equally to the manuscript.

Provenance and peer review
Not commissioned, externally peer reviewed.

Consent
All patients provided written informed consent.

Declaration of competing interest
None. * chi-square test p < 0.05.