Comparative Efficacy of Tegoprazan vs Esomeprazole/Sodium Bicarbonate for the Treatment of Helicobacter pylori Infection

INTRODUCTION: Potassium-competitive acid blockers and proton pump inhibitors/sodium bicarbonate can rapidly increase intragastric pH. In this study, we aimed to compare the clinical outcomes of tegoprazan-based and esomeprazole/sodium bicarbonate–based triple therapies in the treatment of Helicobacter pylori infection. METHODS: We retrospectively reviewed the data of patients with H. pylori infection treated with a 14-day tegoprazan-based triple therapy or 14-day esomeprazole/sodium bicarbonate–based triple therapy. The primary end point was the H. pylori eradication rate with first-line treatment in an intention-to-treat analysis. Secondary end points included the eradication rate with first-line therapy in the per-protocol analysis and adverse events associated with eradication therapy. RESULTS: Of the 854 included patients, 435 were treated with tegoprazan-based therapy, and 419 received esomeprazole/sodium bicarbonate–based therapy. In the intention-to-treat population, no significant difference in eradication rate was detected between the tegoprazan-treated and esomeprazole/sodium bicarbonate–treated groups (78.6% [95% confidence interval (CI), 74.6–82.3%] vs 81.4% [95% CI, 77.4–84.9%], P = 0.313). The per-protocol analysis also revealed a similar eradication rate between groups (tegoprazan vs esomeprazole/sodium bicarbonate: 85.5% [95% CI, 81.8–87.5%] vs 87.8% [95% CI, 84.1–90.7%], P = 0.339). However, abdominal discomfort and diarrhea were more common in the esomeprazole/sodium bicarbonate–treated group than in the tegoprazan-treated group (abdominal discomfort: 1.1% vs 3.8%, P = 0.012; diarrhea: 9.9% vs 21.2%, P < 0.001). DISCUSSION: The efficacy of the esomeprazole/sodium bicarbonate–based triple therapy for H. pylori eradication was comparable with that of the tegoprazan-based triple therapy. However, esomeprazole/sodium bicarbonate–based therapy exhibited a higher risk of abdominal discomfort and diarrhea than tegoprazan-based therapy.


INTRODUCTION
In 1989, Unge et al (1) proposed dual therapy, comprising a proton pump inhibitor (PPI) and amoxicillin, for eradicating Helicobacter pylori infection.PPIs have been an essential component of H. pylori eradication regimens (2).Gastric acid inhibition is crucial for increasing the H. pylori eradication rate by stabilizing acid-labile antibiotics in the stomach and increasing the sensitivity of H. pylori to antibiotics (3).Currently, PPI-based triple therapy, which consists of a PPI, amoxicillin, and clarithromycin, is the most popular eradication regimen worldwide (2,4).
There have been attempts to increase the eradication rate by suppressing gastric acid secretion more effectively using potassium-competitive acid blockers (P-CAB), which exert a faster-onset and longer-lasting acid-inhibitory effect than PPIs (5).In a Japanese randomized controlled trial comparing P-CABbased triple therapy with PPI-based triple therapy, vonoprazan, a P-CAB, was shown to increase the H. pylori eradication rate by nearly 17% points when compared with a PPI (6).In a metaanalysis on the comparative efficacy of vonoprazan vs PPI, vonoprazan-based triple therapy exhibited a 1.2-times better eradication rate than PPI-based triple therapy (7).The higher eradication rate of vonoprazan-based triple therapy compared with that of PPI-based triple therapy was due to the superior efficacy of vonoprazan-based triple therapy against clarithromycin-resistant strains.Recently, a multicenter trial conducted in the United States and Europe confirmed that vonoprazan-based triple therapy exerted superior efficacy to that of PPI-based triple therapy (8).In South Korea, tegoprazan, a new P-CAB, was approved in 2021 for treating H. pylori infection (9,10).
Regimens comprising therapeutic agents that can facilitate the efficacy of PPI have been explored, including a combination of PPI and antacids.Most PPIs are administered as enteric-coated formulations, which are necessary to protect the acid-labile PPI from acid degradation in the stomach.Accordingly, PPIs are limited because the absorption and onset of their antisecretory effects may be delayed.To overcome these limitations, an immediate-release formulation without an enteric coating containing PPI and sodium bicarbonate was developed (11,12).Sodium bicarbonate protects uncoated PPIs from degradation by gastric acid, enabling its rapid release and absorption and improving its onset of action (11,12).For example, esomeprazole/

STOMACH
Park et al sodium bicarbonate can rapidly increase the plasma concentration of esomeprazole through sodium bicarbonate-mediated neutralization of gastric acid and stabilization of esomeprazole in the stomach (13).In South Korea, esomeprazole/sodium bicarbonate, which has a faster onset of action than esomeprazole monotherapy, is available for acid-related disorders, such as gastroesophageal reflux disease (14).
Both P-CABs and PPIs/sodium bicarbonate are promising therapeutics for rapid symptom control in patients with gastric acid-related disorders.Tegoprazan and esomeprazole/sodium bicarbonate have been reported to increase the intragastric pH to more than 4 within 1 hour of administration (13,15).In addition, these agents may be effective in H. pylori eradication.However, no previous report has explored the comparative efficacies of P-CABs and PPIs/sodium bicarbonate in H. pylori eradication therapy.In addition, adverse events associated with PPI/sodium bicarbonate-based H. pylori eradication therapy are yet to be established.Therefore, in this study, we aimed to compare the efficacy and adverse events of tegoprazan and esomeprazole/ sodium bicarbonate-based triple therapies in real-world settings.

Study population
Adult patients (aged 19 years or older) with H. pylori infection treated with tegoprazan-based triple therapy or esomeprazole/ sodium bicarbonate-based triple therapy between March 2021 and November 2022 at Kangbuk Samsung Hospital were eligible for study inclusion.Patients with a history of H. pylori eradication therapy or subtotal gastrectomy were excluded.We retrospectively reviewed data on patient demographics, symptoms, upper endoscopic findings, comorbidities, medications, adverse events, and results of H. pylori eradication therapy.The institutional review board of the ethics committee approved this study (Kangbuk Samsung Hospital: KBSMC 2022-11-009).Given the retrospective nature of this study, the need for informed consent was waived.

H. pylori eradication therapy
The tegoprazan-based and esomeprazole/sodium bicarbonatebased eradication regimens were selected according to the (i) acid suppressant (either 50 mg of tegoprazan or 20 mg of rabeprazole) twice daily in combination with 120 mg of bismuth 4 times a day, 500 mg of metronidazole 3 times a day, and 500 mg of tetracycline 4 times a day for 14 days.The success of second-line eradication therapy was evaluated after $4 weeks of treatment.

Study end point and measurements
The primary study end point was the H. pylori eradication rate with first-line treatment in an intention-to-treat (ITT) analysis.
The secondary study end points were as follows: H. pylori eradication rate with first-line therapy in the per-protocol (PP) analysis, eradication rate with second-line treatment in the ITT and PP analyses, and adverse events associated with H. pylori eradication therapy.One or more of the following tests were used to confirm the successful eradication of H. pylori infection: the 13 C-urea breath test (Korea Otsuka Pharmaceutical Co., Ltd, Seoul, Korea) and histological evaluation with modified Giemsa staining.If any of the 2 tests were positive, H. pylori eradication was considered to have failed.
We visually assessed the severity of atrophic gastritis based on the Kimura-Takemoto classification as follows (16): mild (C-1 and C-2), moderate (C-3 and O-1), and severe (O-2 and O-3).Drug adherence was defined as the administration of $80% of

Statistical analysis
Continuous variables, presented as mean 6 SD, were compared using the Student t test.Categorical variables, presented as numbers with proportions, were compared using the Fisher exact test.Patients who did not receive sufficient medication (,80% of the prescribed medications) or were lost to follow-up were considered to have failed to achieve a cure in the ITT analysis.For PP analysis, patients with insufficient medications and those lost to follow-up were excluded.Logistic regression analysis was performed to identify factors associated with the failure of first-line H. pylori eradication therapy.Variables with P values ,0.1 in the univariable logistic regression model were included as covariates in the multivariable analysis.P , 0.05 was deemed statistically significant.Data analyses were conducted using the R statistical software (version 4.2.2;R Foundation for Statistical Computing, Vienna, Austria).

Study population and baseline characteristics
In total, 883 patients who received tegoprazan-based or esomeprazole/sodium bicarbonate-based triple therapy for H. pylori infection were included in this study (Figure 1).After excluding 29 patients with a history of H. pylori eradication therapy or subtotal gastrectomy, 854 patients were included in the ITT analysis.Of them, 435 patients had undergone 14-day tegoprazan-based triple therapy, while 419 patients had received a 14-day esomeprazole/sodium bicarbonate-based triple therapy.After excluding 6 patients with insufficient medication and 64 who were lost to follow-up, 399 and 385 patients in the tegoprazan-treated and esomeprazole/sodium bicarbonatetreated groups, respectively, remained in the PP population.
Second-line H. pylori eradication therapy was administered to 107 patients in whom first-line eradication therapy failed to treat the H. pylori infection.Table 1 summarizes the baseline characteristics of included patients.The mean age was 56.0 6 11.6 years in the tegoprazan group and 57.1 6 10.9 years in the esomeprazole/sodium bicarbonate group (P 5 0.155).The proportion of males was 55.6% and 50.1% in the tegoprazan and esomeprazole/sodium bicarbonate groups, respectively (P 5 0.107).Hypertension was more common in the esomeprazole/sodium bicarbonate group than in the tegoprazan group (28.6% vs 21.6%, P 5 0.018).Antithrombotic agents, particularly aspirin, were more commonly taken by patients in the esomeprazole/sodium bicarbonate group than those in the tegoprazan group (any antithrombotic agent: 12.6% vs 7.1%, P 5 0.007; aspirin: 7.9% vs 3.4%, P 5 0.005).
Table 2 summarizes baseline patient symptoms and endoscopic findings.The most common indication for H. pylori eradication was H. pylori-associated gastritis in both groups (tegoprazan vs esomeprazole/sodium bicarbonate: 83.4% vs 89.5%).Atrophic gastritis was more common in the esomeprazole/sodium bicarbonate group than in the tegoprazan group (96.4% vs 79.3%, P , 0.001).
Considering the 107 patients who received second-line therapy, 83 received 14-day tegoprazan-based bismuth-containing quadruple therapy, while 24 received 14-day rabeprazole-based bismuth-containing quadruple therapy (Figure 2).There were no significant differences between the groups in either ITT

Treatment adherence and adverse events
Table 3 summarizes the adherence and adverse events associated with the first-line H. pylori eradication therapy.Adherence was .90% in both groups (tegoprazan vs esomeprazole/sodium bicarbonate: 91.7% vs 91.9%, P 5 0.932).However, the overall adverse event rate was higher in the esomeprazole/sodium bicarbonate group than that in the tegoprazan group (39.4% vs 28.0%, P , 0.001).Both groups experienced mild or moderate adverse events.Specifically, abdominal discomfort and diarrhea were more common in the esomeprazole/sodium bicarbonate group than in the tegoprazan group (abdominal discomfort: 1.1% vs 3.8%, P 5 0.012; diarrhea: 9.9% vs 21.2%, P , 0.001).
Adherence and adverse events associated with second-line therapy are listed in Supplementary Table S1 (see Supplementary Digital Content, http://links.lww.com/CTG/A991).Although the incidence of most adverse events did not differ between the rabeprazole-based and tegoprazan-based quadruple therapies, the tegoprazan-based quadruple therapy group exhibited a higher incidence of diarrhea than the rabeprazole-based quadruple therapy group (22.8% vs 4.2%, P 5 0.040).
Factors associated with failure of H. pylori eradication Table 4 summarizes the logistic regression model for the failure of first-line H. pylori eradication therapy.Although univariable analysis revealed that sex, smoking habits, and alcohol use were associated with eradication failure, no significant associations were identified after adjusting for confounding variables.In addition, the eradication regimen (tegoprazan-based vs esomeprazole/sodium bicarbonate-based triple therapy) was not independently associated with failure of first-line H. pylori eradication.

DISCUSSION
P-CABs are rapid and potent gastric acid inhibitors that can overcome the limitations associated with PPIs.Therefore, in this study, among the PPI formulations comparable with P-CABs, we selected an immediate-release formulation containing esomeprazole with a strong gastric acid suppression effect and sodium bicarbonate, which enabled rapid onset of action.In this study, our findings revealed that 14-day tegoprazan-based and 14-day esomeprazole/sodium bicarbonate-based triple therapies exhibited similar efficacy in terms of H. pylori eradication rate.Although this study did not include an esomeprazole-based triplet regimen, we could infer the impact of sodium bicarbonate on H. pylori eradication therapy by reviewing the results of previous studies.In an earlier multicenter randomized controlled trial and our real-world study, tegoprazan-based triple therapy showed an eradication rate similar to that of PPI-based triple therapy (9,10).Although P-CAB typically exerts a rapid and potent acidinhibitory effect, the dosage of P-CAB may be critical for achieving a high eradication rate.Although 50 mg of tegoprazan rapidly increases the intragastric pH .4, its ability to maintain the intragastric pH .6 may be weaker than that of vonoprazan (20 mg) (15).Compared with 20 mg of vonoprazan, 50 mg of tegoprazan, which is currently available in South Korea, may be insufficient to ensure a high eradication rate that exceeds PPI therapy (10).Consistently, available evidence indicates that both 50 mg of tegoprazan and the standard dose of PPI similarly affect H. pylori eradication.Therefore, considering the findings of previous studies and those of this study, it can be assumed that esomeprazole/sodium bicarbonate-based triple therapy may have similar efficacy to that of the PPI-based triple therapy.Accordingly, the role of sodium bicarbonate in the treatment of H. pylori infections remains unclear.
Considering the insignificant role of sodium bicarbonate in eradication therapy, it is believed that although sodium bicarbonate can rapidly increase the intragastric pH, it fails to maintain a sustained elevation (11,12).For example, esomeprazole/sodium bicarbonate can reduce the time required to increase the intragastric pH to ˃4 by approximately 1 hour when compared with esomeprazole alone; however, it does not increase the duration of time for which the intragastric pH remains ˃6 (13).Another study attempted to increase the eradication rate by increasing the intragastric pH with PPI before initiating eradication therapy; however, no improvement in eradication rate was observed (18).Therefore, it is unlikely that simply elevating the intragastric pH at the start of eradication therapy by using sodium bicarbonate to raise the pH rapidly will improve the eradication rate.
Additional adverse events may be a concern when using sodium bicarbonate as an adjunct to H. pylori eradication therapy.The risk of abdominal discomfort and diarrhea was approximately 2-3 times higher in the esomeprazole/sodium bicarbonate group than that in the tegoprazan group.Generally, the ingestion of sodium bicarbonate results in the production of CO 2 gas owing to the dehydration of carbonic acid dissolved in water (19).Although CO 2 is slowly produced in the stomach, it can cause abdominal bloating or cramping (19).Furthermore, sodium bicarbonate can alter the pH of the small intestine.Consequently, altered pH may result in dysbiosis in the small intestine.This may make patients taking esomeprazole/sodium bicarbonate more susceptible to antibiotic-associated diarrhea than those taking tegoprazan.Adherence was similarly high in both groups because most of the adverse events were mild and resolved spontaneously.Nevertheless, the high risk of adverse events associated with esomeprazole/ sodium bicarbonate therapy weakens the rationale for treating H. pylori infection with esomeprazole/sodium bicarbonate.
In this study, sodium bicarbonate was not included as a secondline regimen.The second-line tegoprazan-based and rabeprazolebased quadruple therapies exhibited similar overall eradication rates.The overall adverse event rates were similar between the groups.However, diarrhea was more common in patients receiving tegoprazan-based quadruple therapy than in those receiving rabeprazole-based quadruple therapy.Considering the high risk of diarrhea with bismuth-containing quadruple therapy (10), the incidence of diarrhea with second-line rabeprazole-based quadruple therapy in this study (4.2%) was relatively low.Although the underlying cause for this inconsistency remains unclear, it could be explained by the relatively high proportion of patients who received first-line esomeprazole/sodium bicarbonate-based triple therapy in the second-line rabeprazole-based quadruple therapy group.Diarrhea may have been underestimated in these patients, given that several patients had already experienced diarrhea during the first-line treatment with sodium bicarbonate.
Our logistic regression analysis did not identify any factors associated with the failure of the first-line treatment.If we consider only the efficacy of eradication therapy, tegoprazan-based triple therapy or esomeprazole/sodium bicarbonate-based triple therapy can be selected.However, considering the risk of adverse events, tegoprazan-based triple therapy may be a better option than esomeprazole/sodium bicarbonate-based triple therapy.
However, this study is the first to investigate the efficacy of P-CAB-based triple therapy with PPI/sodium bicarbonate-based triple therapy; however, the limitations need to be addressed.First, this was a single-center retrospective study.Although our study can help understand real-world practice in patients receiving tegoprazanbased or esomeprazole/sodium bicarbonate-based triple therapy, some data, such as adverse events, particularly those related to second-line treatment, may be underestimated.Second, we could not consider the antibiotic resistance status.According to the current Korean guidelines, empirical triple therapy is allowed when the antibiotic resistance status is unknown (20).Therefore, our real-world study could only be performed in an empirical treatment setting without knowing the antibiotic resistance status.In a recent nationwide prospective study, the clarithromycin resistance rate of H. pylori in Korea was 17.8% (21).The high rate of clarithromycin resistance may have contributed to the poor H. pylori eradication rate observed in this study.Although we assumed that the clarithromycin resistance rate would be similarly high between the 2 study groups, we could not evaluate the clarithromycin resistance rate in our study because of the retrospective nature of the study design.Third, our study was conducted in Korea, where a high clarithromycin resistance rate has been recorded.Therefore, generalization of our study findings to other countries should be cautious.Despite these limitations, our study provides a better understanding of the comparative efficacy of tegoprazan-based and esomeprazole/sodium bicarbonate-based triple therapies for the treatment of H. pylori infection in a real-world setting.The eradication rate did not differ between the 2 therapies; however, esomeprazole/sodium bicarbonate-based triple therapy was associated with a higher incidence of adverse events, including abdominal discomfort and diarrhea, than tegoprazan-based triple therapy.

Table 1 .
Baseline characteristics of included patients

Table 2 .
Baseline symptoms and endoscopic findings EGC, early gastric cancer; ESD, endoscopic submucosal dissection; MALT, mucosa-associated lymphoid tissue.aRefluxsymptoms include heartburn and acid regurgitation.bOthersymptoms include globus sensation, anorexia, and belching.cThereare 2 missing values for nodular gastritis and atrophic gastritis in the triple therapy group.dSeverity of atrophic gastritis is determined by the Kimura-Takemoto classification (15).Clinical and Translational GastroenterologyVOLUME 14 | NOVEMBER 2023 www.clintranslgastro.comSTOMACH Park et al prescribed medications.The severity of adverse events was assessed as mild (transient symptoms that improved spontaneously), moderate (symptoms that required management), or severe (symptoms that led to emergency visits) (17).
Supplementary Digital Content, http://links.lww.com/CTG/A990).We further analyzed previous eradication regimens in patients who received second-line therapy.Of the 83 patients who received tegoprazan-based quadruple therapy as second-line treatment, 52 (62.7%) received tegoprazan-based triple therapy and 31 (37.3%) received esomeprazole/sodium bicarbonatebased triple therapy as first-line treatment.Conversely, of the 24 patients who received rabeprazole-based quadruple therapy, 15

Table 3 .
Adherence and adverse events of first-line H. pylori eradication therapy a Adherence is determined as administration of $80% of prescribed medications.b Percentage is calculated based on the ITT population.c Other adverse events include insomnia, dry mouth, and sores on the tongue.Clinical and Translational Gastroenterology VOLUME 14 | NOVEMBER 2023 www.clintranslgastro.comSTOMACH

Table 4 .
Factors associated with failure of first-line H. pylori eradication a American College of GastroenterologyClinical and Translational GastroenterologySTOMACHTegoprazan vs Esomeprazole/Sodium Bicarbonate in H. pylori Eradication

Table 4 .
[14]tinued), body mass index; EGC, early gastric cancer; ESD, endoscopic submucosal dissection; MALT, mucosa-associated lymphoid tissue; OR, odds ratio; CI, confidence interval; N/A, not applicable.This analysis is performed on participants who received a follow-up test for H. pylori eradication.bRefluxsymptomsinclude heartburn and acid regurgitation.Other symptoms include insomnia, dry mouth, and sores on the tongue.dSeverity of atrophic gastritis is determined by the Kimura-Takemoto classification[14].