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Eradication Rates for Esomeprazole and Lansoprazole-Based 7-Day Non-Bismuth Concomitant Quadruple Therapy for First-Line Anti-Helicobacter pylori Treatment in Real World Clinical Practice

Authors Hung KT, Yang SC, Wu CK, Wang HM, Yao CC, Liang CM, Tai WC, Wu KL, Kuo YH, Lee CH, Chuah SK

Received 31 January 2021

Accepted for publication 6 March 2021

Published 25 March 2021 Volume 2021:14 Pages 1239—1246

DOI https://doi.org/10.2147/IDR.S304711

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Héctor M. Mora-Montes


Kuo-Tung Hung,1 Shih-Cheng Yang,1 Cheng-Kun Wu,1,2 Hsing-Ming Wang,1 Chih-Chien Yao,1 Chih-Ming Liang,1,2 Wei-Chen Tai,1,2 Keng-Liang Wu,1,2 Yuan-Hung Kuo,1,2 Chen-Hsiang Lee,2,3 Seng-Kee Chuah1,2

1Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 2Chang Gung University, College of Medicine, Taoyuan, Taiwan; 3Division of Infectious Disease, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan

Correspondence: Seng-Kee Chuah; Chih-Ming Liang
Division of Hepatogastroenterology, Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung, 833, Taiwan
Tel + 886-7-7317123 ext. 8301
Fax + 886-7-7322402
Email [email protected]; [email protected]

Purpose: Non-bismuth concomitant quadruple therapy is commonly administered in Taiwan, achieving an acceptable efficacy as a first-line anti-Helicobacter pylori treatment. This study compared the eradication rates between esomeprazole- and lansoprazole-based non-bismuth concomitant quadruple therapy for first-line anti-H. pylori treatment.
Patients and Methods: This study included 206 H. pylori-infected naïve patients between July 2016 and February 2019. The patients were prescribed with either a 7-day non-bismuth containing quadruple therapy (esomeprazole, 40 mg twice daily; amoxicillin, 1 g twice daily; and metronidazole, 500 mg twice daily; and clarithromycin, 500 mg twice daily for 7 days [EACM group]; lansoprazole, 30 mg twice daily; amoxicillin, 1 g twice daily; metronidazole, 500 mg twice daily; and clarithromycin, 500 mg twice daily [LACM group]). Then, the patients were asked to perform urea breath tests 8 weeks later.
Results: The eradication rates in the EACM group were 86.1% (95% confidence interval [CI], 77.8%– 92.2%) and 90.6% (95% CI, 82.9%– 95.6%) in the intention-to-treat (ITT) and the per-protocol (PP) analyses, respectively. Moreover, the eradication rates in the LACM group were 90.1% (95% CI, 82.6%– 95.2%) and 92.6% (95% CI, 85.5%– 96.9%) in the ITT and the PP analyses, respectively. Consequently, the LACM group exhibited more diarrhea patients than the EACM group (7.1% versus 1.0%, p = 0.029), but all symptoms were mild. Univariate analysis in this study showed that metronidazole-resistant strains were the clinical factor affecting the eradications (95.3% versus 78.9%, p = 0.044). Moreover, a trend was observed in dual clarithromycin- and metronidazole-resistant strains (91.5% versus 66.7%, p = 0.155).
Conclusion: The eradication rates between esomeprazole and lansoprazole-based non-bismuth concomitant quadruple therapy for first-line H. pylori treatment were similar in this study. Both could achieve a > 90% report card in the PP analysis.

Keywords: Helicobacter pylori, esomeprazole, lansoprazole, concomitant therapy, antibiotic resistance

Introduction

Helicobacter pylori infection is an important worldwide public health issue with a prevalence of 45.2%–84.2%.1 Patients can develop chronic gastritis, atrophic gastritis, intestinal metaplasia, dysplasia, gastric cancer, and peptic ulcer disease when infected.2–6 Hence, successful eradication of H. pylori reduces the recurrence of peptic ulcers and gastric cancer.7–9 The current guidelines and consensus of H. pylori management suggested a concomitant therapy (standard proton pump inhibitor (PPI); amoxicillin, 1 g twice daily; metronidazole, 500 mg twice daily; and clarithromycin, 500 mg twice daily) as first-line regimens.8,10,11 One of the crucial key points for successful H. pylori eradication is securing and lengthening the duration of high intra-gastric pH. A strong acid-suppressing effect drug, vonoprazan, maintains a much higher intra-gastric pH than the traditional PPIs. However, this drug is not available worldwide.12,13

In real-world practice, a twice daily PPI is currently prescribed to patients because it is allowed by the National Health Insurance policy. Therefore, whether different PPIs influence and affect the outcome of H. pylori eradication in this concomitant regimen is an important concern among physicians and patients. Therefore, this study was conducted to compare the eradication rates and adverse effects of esomeprazole- and lansoprazole-based 7-day non-bismuth concomitant quadruple therapy for first-line anti-Helicobacter pylori treatment.

Patients and Methods

Patients

We retrospectively analyzed a total of 206 H. pylori-infected naïve patients from our prospectively collected patients’ registrar profile who were ≥ 20 years old between July 2016 and July 2019 at outpatient clinics in Kaohsiung Chang Gung Memorial Hospital, Taiwan. All patients received an endoscopy that showed either peptic ulcers or gastritis. H. pylori infection was diagnosed by histological assessment of endoscopic biopsy specimens or of gastric mucosa or rapid urease test. All patients were treated with a 7-day non-bismuth concomitant quadruple therapy (esomeprazole, 40 mg twice daily; amoxicillin, 1 g twice daily; metronidazole, 500 mg twice daily; and clarithromycin, 500 mg twice daily for 7 days [EACM group, n = 105] or lansoprazole, 30 mg twice daily; amoxicillin, 1 g twice daily; metronidazole 500 mg twice daily; and clarithromycin 500 mg twice daily [LACM group, n = 101]). For peptic ulcer patients, PPIs or mucosa protectants was prescribed for 4–6 weeks after 7-day non-bismuth concomitant quadruple therapy. However, in a few patients, PPI maybe need for 8 weeks if symptoms were not totally improved. An endoscope follow-up examination would be performed then. No matter how, all of them stop PPI for 2 weeks before taking a UBT test. Patients with a history of previous H. pylori eradication, antibiotics administration within 3 months before endoscopy, gastric malignancy, lost to follow-up, or demonstrated incomplete records were excluded.

Culture and Antimicrobial Susceptibility Testing

H. pylori strains were tested for susceptibility to amoxicillin, clarithromycin, levofloxacin, tetracycline, and metronidazole using the Epsilometer test method (AB Biodisk, Solna, Sweden). H. pylori strains exhibited MIC values of ≥0.5, ≥1, ≥1, ≥4, and ≥8 mg/L, which were considered to be the resistance breakpoints for amoxicillin, clarithromycin, levofloxacin, tetracycline, and metronidazole, respectively, according to the European Committee on Antimicrobial Susceptibility Testing.14

Outcome Measurements and Follow-Up

Follow-up studies to assess treatment responses were carried out for 1 week for drug compliance and adverse events assessment and 8 weeks later for H. pylori testing by urea breath tests. The primary outcome of this study was the eradication rate by intention-to-treat (ITT) and per-protocol (PP) analyses of the two therapeutic groups. Eradication therapy failure was confirmed after treatment by a positive 13C-urea breath test 8 weeks after treatment. Poor compliance was the failure to finish 80% of all medication due to adverse effects.15,16 The secondary outcomes were drug compliance and adverse events. In the PP analysis, patients who were lost during follow-up or did not follow the protocol or with unknown H. pylori status posttherapy were excluded. Adverse events (abdominal pain, constipation, diarrhea, dizziness, headache, nausea/vomiting, and skin rash) were compared.

Statistical Analysis

Statistical analysis was performed using the Statistical Package for the Social Sciences, version 22, for windows. Moreover, a P value of <0.05 was considered statistically significant. The 95% confidence interval (CI) was constructed by normal approximation. Univariate logistic regressions were performed to predict successful eradication.

Results

Baseline Characteristics and H. pylori Eradication Rates

The patient deposition is shown in Figure 1. Six and three patients were lost to follow-up, respectively, in the EACM and LACM groups among the 206 patients enrolled in the ITT. Finally, 99 and 98 patients were included in EACM and LACM groups for PP analysis, respectively. The baseline characteristics were similar between the two groups in age, gender, social habits, and endoscopic findings (Table 1). The eradication rates in the EACM group were 86.1% (95% CI, 77.8%–92.2%) and 90.6% (95% CI, 82.9%–95.6%) in the ITT and PP analyses, respectively. Moreover, the eradication rates in the LACM group were 90.1% (95% CI, 82.6%–95.2%) and 92.6% (95% CI, 85.5%–96.9%) in the ITT and PP analyses, respectively (Table 2). The adverse events were also similar between the two groups (11.1% versus 10.2%, p = 0.837; Table 2). However, more diarrhea symptoms were observed in the LACM than in the EACM group (7.1% versus 1.0%, p = 0.029; Table 3). Other adverse events included abdominal pain (4.0% and 3.1%), nausea sensation (3.1% and 2.0%), dizziness (1% in both groups), and headache (3% and 1%). Univariate analysis showed that metronidazole-resistant strains were the clinical factor affecting the eradications in this study (95.3% versus. 78.9%, p = 0.044). A trend was observed in dual clarithromycin- and metronidazole-resistant strains (91.5% versus 66.7%, p = 0.155; Table 4).

Table 1 Demographic Data and Endoscopic Appearance of Two Patient Groups

Table 2 The Major Outcomes of Two Period’s Groups

Table 3 Adverse Events of Two Groups

Table 4 Univariate Analysis of the Clinical Factors Influencing the Efficacy of H. pylori Eradication Therapy

Figure 1 Patients’ deposition.

Abbreviations: EACM, 7-day esomeprazole-based non-bismuth concomitant quadruple therapy; LACM, 7-day lansoprazole-based non-bismuth concomitant quadruple therapy; ITT, Intention-to-treat; PP, per-protocol.

Antibiotic Resistance

The H. pylori strains were tested for susceptibility to antibiotics in 68 patients, the positive culture rate was 91.2% (62/68). Antibiotic resistances were 14.5%, 30.6%, and 35.5% clarithromycin, metronidazole, and levofloxacin, respectively. Moreover, 4.8% of them exhibited dual resistant clarithromycin and metronidazole. No antibiotic-resistant strain to amoxicillin and tetracycline was noted in this study (Figure 2).

Figure 2 Antibiotic resistances in the patients.

Abbreviations: AMX, amoxicillin; CLA, clarithromycin; MET, metronidazole; LFX, levofloxacin; TC, tetracycline; MET-CLA, dual metronidazole and clarithromycin resistance.

Among patients with the amoxicillin- and clarithromycin-susceptible strains, the H. pylori eradication rate was 90.6% (48/53) and 88.9% (8/9) for those with clarithromycin-resistant strains. The eradication rate was 78.9% (15/19) for patients with metronidazole resistance assigned to both the concomitant therapy groups.

Discussion

Conferring to the Maastricht V and Taiwanese consensus, concomitant therapy for 7–14 days was recommended as one of the first-line therapies for H. pylori eradication.8,11 Achieving an acceptable eradication rate for naïve H. pylori infection was its benefit with the advantages of convenience and easy-to-adhere one-stage combination formulation instead of the two-stage sequential and hybrid therapies.17–20 The differences between PPIs in H. pylori eradication triple therapy were compared, and the results were debatable after several decades.21,22 Most head to head comparison studies were based on comparisons among standard triple therapy. The H. pylori eradication rate in esomeprazole was better than the first-generation PPIs (omeprazole, lansoprazole, and pantoprazole) in the standard triple therapy.23 This result was often explained by the prominent effect of esomeprazole to control gastric pH level and the CYP2C19 effect on metabolization of PPIs. However, rare studies existed comparing eradication rates between different kinds of PPI in non-bismuth concomitant quadruple therapy for first-line H. pylori.

The eradication rates between esomeprazole- and lansoprazole-based non-bismuth containing quadruple therapy for first-line H. pylori treatment were similar in this study and achieved a 90% report card in the PP analysis. Heterogeneous results regarding the head to head comparisons between esomeprazole and lansoprazole have been reported in the literature. Wilder-Smith et al reported that the stronger acid suppression performance in esomeprazole compared with lansoprazole in standard dose (esomeprazole [40 mg daily] versus lansoprazole [30 mg daily]).24 Graham et al reported similar potencies of esomeprazole and lansoprazole at a 20 mg:45 mg ratio after standardizing PPI potency in terms of the duration of intra-gastric pH > 4/24 h (pH4 time).25 One other report documented the impact of the CYP2C19 genotype on pharmacokinetic parameters for esomeprazole presenting with a smaller effect on the area under the curve (AUC) than other PPIs (omeprazole and lansoprazole).26 The latter could explain why the esomeprazole-based concomitant therapy was not superior in treatment success compared with lansoprazole-based concomitant treatment regimens in the current study. Other possible reasons could be that the rate of CYP2C19 rapid metabolizers was proven to be higher in Europe and North America (56%–81%) compared with the Asian population (27%–38%).27 The lower potent PPIs, such as lansoprazole, could be enough for acid suppression in the concomitant regiment in Asia. In addition, metronidazole is relatively stable in low pH gastric juice compared to clarithromycin.28,29 The additional metronidazole in the quadruple than in the triple therapy may overcome the influence of lower acid suppression in the LACM group. In China, Chen et al reported no difference between esomeprazole (20 mg BID) and lansoprazole (30 mg BID) in the eradication rate of H. pylori in the 14-day bismuth-furazolidone quadruple regiment.30 Boltin et al reported the esomeprazole did not show a significant trend over omeprazole among subjects receiving quadruple therapy.31 These reports were similar with to the current findings. Thus, concomitant quadruple therapies could achieve good eradication efficacy in case of less potency in acid suppression of PPIs.

Studies reported that dual clarithromycin and metronidazole resistance undermines the efficacy of concomitant therapy. Cure rates with sequential, hybrid, and concomitant therapy will always be <90% when the rates of dual resistant strains are >5%, >9%, or >15%, respectively.8,32 Thus, antibiotic resistance is one of the most important factors that determine eradication success. The data in this study also showed a lower eradication rate in the dual resistant group compared with the dual-sensitive group (91.5% vs 66.7%, p = 0.155). A progressively higher resistance rate was observed for clarithromycin (11.8–20.4%, p = 0.039) and metronidazole (25.6–42.3%, p < 0.001) among patients who received first-line eradication therapy in 7 years was observed in the cohort antibiotics resistance study in Taiwan. Furthermore, the primary dual resistance to clarithromycin and metronidazole also significantly increased in a linear trend from 2.4% to 10.4% (p = 0.009).33 The eradication rate of non-bismuth concomitant quadruple therapy in first-line therapy could be expected to drop further to < 90% in Taiwan as time goes by. Therefore, continuously monitoring regional resistance rates was mandatory. Recent studies reported a novel potassium-competitive acid blocker (vonoprazan) that provides a stronger and longer-lasting effect on gastric acid suppression than other PPIs.34 Vonoprazan-based regimens is more useful than the PPI-based regimen as a first-lineH. pylori eradication therapy.35 Furthermore, the effectiveness for patients infected with clarithromycin-resistant strains was demonstrated in patients living in areas where clarithromycin-resistant strain prevalence is >15%.36

This study exhibits several limitations. First, antibiotic susceptibility tests were not performed in all patients, and only 68 of 206 patients exhibited an antibiotic susceptibility test. However, no difference in antibiotic resistance exists between the EACM and LACM groups. Second, this was a retrospective study in a single medical center.

Conclusion

The eradication rates between esomeprazole- and lansoprazole-based non-bismuth concomitant quadruple therapy for first-line H. pylori treatment were similar in this study. Both could achieve a >90% report card in the PP analysis.

Data Sharing Statement

No data will be shared except besides what is included in the manuscript.

Ethics Approval and Informed Consent

This protocol was approved by the institutional review board and the Ethics Committee of Chang Gung Memorial Hospital (IRB-202002020B0D001). The Ethics Committee waived the requirement for informed consent for this retrospective study and all the data were analyzed anonymously. None of our patients were minors or children. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee.

Acknowledgments

The authors would like to acknowledge Miss Ching-Yi Lin for the assistance in this study.

Author Contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Funding

There is no funding to report.

Disclosure

The authors report no conflicts of interest exist in this work.

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