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The Efficacy of Potassium Competitive Acid Blocker-based First-line Triple Therapy on Helicobacter pylori Eradication as Compared to Proton Pump Inhibitor-based Treatment: A Systematic Review and Meta-analysis
Yakhak Hoeji 2022;66(6):374-382
Published online December 31, 2022
© 2022 The Pharmaceutical Society of Korea.

Miryoung Kim*, Sola Han**, and Hae Sun Suh**,***,#

*College of Pharmacy, Pusan National University
**College of Pharmacy, Kyung Hee University
***Department of Regulatory Science, Kyung Hee University
Correspondence to: Hae Sun Suh, 26, Kyunghee-daero, Dongdaemun-gu, Seoul 02447, Republic of Korea
Tel: +82-2-9619492, Fax: +82-2-9619580
E-mail: haesun.suh@khu.ac.kr
Received August 8, 2022; Revised September 21, 2022; Accepted December 8, 2022.
Abstract
Although randomized controlled trials (RCTs) comparing potassium competitive acid blockers (PCABs) and proton-pump inhibitors (PPIs) have been previously conducted, systematic reviews are lacking. In this systematic review and meta-analysis, we searched the CENTRAL, EMBASE, MEDLINE, KMBASE, and KoreaMed databases for relevant RCTs up to October 3, 2020. We assessed the Helicobacter pylori eradication rate of PCAB-based first-line triple therapy and compared it with that of PPI-based therapy. In all five of the included studies comprising a total of 1542 patients, the intervention used was vonoprazan (VPZ)-based therapy, and there were no studies on tegoprazan (TPZ)-based therapy. The pooled risk ratios (RRs) for the eradication rate of VPZ-based therapy as compared to those of PPI-based therapies was 1.17 (95% confidence interval (CI): 1.10–1.26, P<0.00001 for overall effect, I2=41%, P=0.15 for heterogeneity). The RR of VPZ-based therapy compared to that of PPI-based for clarithromycin (CAM)-resistant strains was 1.29 (95% CI: 1.12–1.48, P<0.0003 for overall effect, I2=0%, P=0.78 for heterogeneity). VPZ-based first-line triple therapy shows a significant H. pylori eradication rate compared to that of the PPI-based. Notably, VPZ-based therapy shows a better eradication rate than that PPI-based therapy, even in patients with CAM-resistant strains.
Keywords : Helicobacter pylori, Disease Eradication, Gastric Disease, Proton Pump Inhibitors
Introduction

Helicobacter pylori (H. pylori) infection is a known risk factor for many gastrointestinal diseases, including peptic ulcer, chronic gastritis, gastric mucosa-associated lymphoid tissue lymphoma, and gastric cancer.1-6 H. pylori eradication reduces the incidence of gastric diseases7-9 and is a cost-effective strategy for preventing gastric diseases.10,11 Unfortunately, the H. pylori eradication rate has been steadily decreasing.12,13 Although the reason for this is unclear, many studies have indicated that one of the reasons is associated with increased antibiotic resistance.14-16 According to a review article, clarithromycin (CAM) resistance has rapidly increased in China, Japan, Korea, Italy, and the US.16 In almost all countries, CAM resistance rates exceed the threshold for altering therapeutic interventions. The most widely used treatment regimen for first-line H. pylori eradication is the proton pump inhibitor(PPI)-based triple therapy with amoxicillin (AMX), CAM, or metronidazole (MTZ). Furthermore, this regimen is suggested by the treatment guideline of the American Journal of Gastro-enterology.3 However, PPIs may be insufficient to maintain an adequate intragastric pH for 24 h to achieve the effect of antibiotics.17 When the intragastric pH increases, acid-labile antibiotics, such as CAM, are unable to reach higher concentrations for a sufficient time and are relatively less effective for H. pylori eradication.17

Potassium competitive acid blockers (PCABs) have been approved for the treatment of acid-related diseases in East Asia since 2015. PCABs have a different mechanism of action than PPIs as they do not need to be transformed into their active form. PCABs inhibit gastric H+/K+-ATPase, independent of acid levels.18,19 The most commonly used PCABs are vonoprazan (VPZ) and tegoprazan (TPZ). VPZ showed a greater acid-inhibitory effect and a longer proportion of pH 4 holding time than PPIs, and it can accumulate in high concentrations in intracellular canaliculi.20-24 TPZ inhibits gastric acid secretion faster and more potently than PPIs.18 Based on improved acid suppression, PCABs have been proposed as a new therapeutic approach for H. pylori eradication, instead of PPIs, especially considering that antibiotic resistance has been increasing in Japan.25 In addition, PCABs showed a high eradication rate, even in patients with antibiotic resistance.26-28 Although randomized controlled trials (RCTs) reporting the efficacy of PCABs compared to PPIs have been published, systematic reviews evaluating its efficacy on H. pylori eradication are scarce. Only two systematic reviews have been published: one review included one full-text RCT and nine retrospective studies,29 and the other review included three full-text RCTs.30 In circumstances where notable new drugs are being used to treat H. pylori infections, it is essential to evaluate evidence for the efficacy of PCABs.

The objective of this study was to assess the H. pylori eradication rates of PCAB-based first-line triple therapies and to compare these to those of PPI-based first-line triple therapies, including the latest RCTs.

Methods

Search Strategy

We searched the electronic databases of MEDLINE (1946 to September 3, 2020, via Ovid), EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), KMBASE, and KoreaMed for relevant RCTs up to October 3, 2020. The search was conducted in all languages. The search terms were “Helicobacter pylori” AND “proton pump inhibitors” AND “vonoprazan OR tegoprazan” AND “randomized controlled trial”. For more details of information on search terms can be seen in the Supplementary file.

Inclusion and Exclusion Criteria

The inclusion criteria were as follows: 1) RCTs published as full-text or abstract-only; 2) studies including patients diagnosed with H. pylori infections; 3) the first-line H. pylori eradication triple therapy with two antibiotics as concomitants; 4) the intervention was VPZ or TPZ; 5) the comparator was PPI regardless of the treatment period; and 6) The outcome was the eradication rate confirmed by a urea breath test (UBT). Animal studies, reviews, and case reports were excluded. Two authors (MR Kim, Sola Han) independently screened the titles and abstracts to identify studies that met the inclusion criteria. Any disagreement was resolved by a discussion with a third author (HS Suh). We documented the selection process in sufficient detail to complete the PRISMA 2020 flow.31

Data Extraction

Two independent reviewers (MR Kim and Sola Han) extracted the data using a pre-designed data extraction form. Any disagreements were discussed with the third review author (HS Suh). Data, including the year of publication, country, study design, number of subjects, dosage, duration of treatment, confirmative test for eradication, and eradication rate, were extracted from the eligible studies. Where intention-to-treat (ITT) data were available, we preferred ITT data over per-protocol (PP) data.

Risk of bias

The risk of bias was assessed using the Cochrane Collaboration tool (RoB version 1.0).32 Although RoB version 2.0 is the newest version of the Cochrane RoB Tool, we used the RoB version 1.0 Tool since it is a widespread tool, providing more comprehensive information on the risk of bias. RoB version 1.0 includes the following seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias. The risk of bias was assessed by assigning judgments of low, high, or unclear risk of bias. Two independent investigators (MR Kim and Sola Han) performed the assessment, and the third review author (HS Suh) resolved disagreements.

Statistical Analysis

A meta-analysis was performed to calculate the pooled risk ratio (RR) for the H. pylori eradication rate of PCAB-based first-line triple therapy, as compared to that of PPI-based first-line triple therapy. The Mantel-Haenszel method was used to combine the RRs for H. pylori eradication rates. We calculated the RR and 95% confidence interval (CI) using random- and fixed-effect models. If the p-value was <0.05, we considered the level of significance to be significant, except for the heterogeneity test. Statistical heterogeneity was assessed using the Cochran’s Q-test (p-value <0.1, indicating significant heterogeneity) and I2 statistics (<25%, 25%-50%, and >50% indicating low, moderate, and high heterogeneities, respectively).33 To explore the causes of heterogeneity, we performed subgroup analyses according to comparators, study design, risk of bias, and CAM strains. The result was mainly presented by the random-effect models since it allows for the possibility that studies have heterogeneous effects. Publication bias was not assessed because the number of included studies was <10. Study selection and data extraction were done through EndNote X9.3.3. (Clarivate Analytics) and Microsoft Excel, respectively. All analyses were performed using RevMan version 5.4.1 (Cochrane Collaboration, Copenhagen, Denmark) by forest plots. This review was performed according to the PRISMA guidelines,31 and the PRISMA 2020 checklist was presented in the Supplementary file. The protocol was registered in PROSPERO (CRD 42022296637).

Results

Study Selection and Data Collection

As shown in Fig. 1, 176 studies were identified through the search. Of these, we excluded 38 duplicate studies and 127 studies that did not meet the eligibility criteria. Subsequently, two further studies were excluded, including an interim study by the same researcher34 and an incomplete study.35 Ultimately, only five eligible studies remained for the quantitative analysis.36-40



Fig. 1. The PRISMA 2020 flow diagram. PICOs, Patients, interventions comparisons and outcomes.

Characteristics of the Included Studies

The intervention in all five included studies was VPZ-based therapy, and there was no study on TPZ-based therapy (Table 1). All the studies were conducted in Japan. The years of publication ranged from 2016 to 2019. Regarding the comparators (PPIs), two studies utilized rabeprazole (RPZ),38,39 three studies used lansoprazole (LPZ),36,38,39 and three studies utilized esomeprazole (EPZ).37,39,40 In all studies, the concomitants were 750-mg AMX and 200-400-mg CAM twice daily for 7 days. All five studies were RCTs (three full-text36,38,39 and two abstract-only articles).37,40 There were three types of study designs: one double-blind,36 one single-blind,38 and three open-label studies.37,39,40 Except for one study that did not mention the test timing,37 eradication success was confirmed at least 4 weeks after finishing therapy using UBT. Two studies included the eradication rates for CAM-resistant and CAM-susceptible patients by post hoc analyses.36,40 The baseline characteristics of included studies were similar: the mean age of the population was between 50 and 60 years old, and female was between 30 and 40%. These results of baseline characteristics are shown in Table 1.

Characteristics of the studies included

First author Year Country Age (years) Female (%) Study design, Publication (full or abstract) Number of subjects (completed/enrolled) Dose and frequency (twice a day) Duration of treatment Time to test after therapy Eradication rates (VPZ vs. PPIs)
Intervention PCAB Comparators PPIs Concomitant antibiotics
Murakami K et al.36) 2016 Japan I: 55±12.3
C: 53.9±12.9
I: 40.4%
C: 39.5%
Double-blind, full 641/650 VPZ 20 mg LPZ 30 mg AMX 750 mg, CAM 200 or 400 mg 7 days ≥4 weeks 91.2% vs 75.7%
Sasaki H et al.37) 2016 Japan NA NA Open-label, abstract 100/110 VPZ 20 mg EPZ 20 mg AMX 750 mg, CAM 200 mg 7 days NA 93.0% vs 83.7%‡
Maruyama M et al.38) 2017 Japan I: 58
C: 60
I: 43%
C: 42%
Single-blind, full 133/141 VPZ 20 mg LPZ 30 mg or RPZ 20 mg AMX 750 mg, CAM 200 or 400 mg 7 days 8 weeks 95.8% vs 69.6%
Sue S et al.39) 2018 Japan I: 64.3±12.3
C: 61.9±13.3
I: 32%
C: 31%
Open-label, full 140/147 VPZ 20 mg LPZ 30 mg or RPZ 10 mg or EPZ 20 mg AMX 750 mg, CAM 200 or 400 mg 7 days 4 weeks 87.3% vs 76.5%
Tamaki H et al.40) 2019 Japan NA NA Open-label, abstract 521/535 VPZ 20 mg EPZ 20 mg AMX 750 mg, CAM 200 mg 7 days ≥8 weeks 83.7% vs 75.7%

NA, not available; PCAB, potassium competitive acid blocker; PPIs, proton pump inhibitors; VPZ, vonoprazan; LPZ, lansoprazole; EPZ, esomeprazole; RPZ, rabeprazole; AMX, amoxicillin; CAM, clarithromycin; I, Intervention; C, Comparators.

The eradication rates were analyzed on intention-to-treat analysis

The eradication rates were analyzed on per-protocol analysis



Risk of Bias Assessment

The results of the risk of bias assessment of the included studies are shown in Fig. 2. One double-blind study was considered as having a low risk in all domains.36 One study was classified as having a high risk of random sequence generation.38 The randomization in this study was based on the personal medical record number: odd number for the PPI group and even number for the VPZ group. Allocation concealment was also considered as having a high-risk, because the allocated groups can be predicted by the physicians. Two studies were considered as having an unclear risk for selection bias.37,40 Although they mentioned “randomly,” there was no detailed information on the sequence generation and concealment. In all two abstract-only articles, selection bias was considered as a high risk because there was no information on the randomization process. Three open-label studies were classified as having a high risk of blinding participants and personnel.37,39,40 Since the missing data rate was >5%, three studies were classified as having a high risk of attrition bias.38,39



Fig. 2. Risk of bias graph. Green (+), low risk of bias; yellow (?), unclear risk of bias; red (-), high risk of bias.

Main Meta-Analysis

The only comparison that we considered was VPZ-based triple therapy versus PPI-based triple therapy, because the intervention in all included studies was VPZ-based triple therapy. The pooled H. pylori eradication rate was higher in the VPZ-based first-line triple therapy (90.2%, 95% CI: 84.3%-96.1% by ITT and 90.4%, 95% CI: 84.6%-96.3% by PP) than in the PPI-based first-line triple therapy (76.2%, 95% CI: 70.0%-82.5% by ITT and 79.1%, 95% CI: 71.5%-86.7% by PP). The results of the meta-analysis by the random- and the fixed-effect models were similar. We found that the VPZ-based first-line triple therapy had a significantly higher eradication rate than the PPI-based first-line triple therapy: the RR for eradication rate was 1.17 by ITT (95% CI: 1.10-1.26, p<0.00001) and 1.14 by PP (95% CI: 1.05-1.25, p=0.003) with the random-effect models (Fig. 3A). The results of the meta-analysis showed moderate heterogeneity (I2=41%, p=0.15, by ITT). Given that the ITT data were not available in only one study, we adopted data from PP.36



Fig. 3. Forest plot of the efficacy of Vonoprazan-based triple therapy vs. Proton pump inhibitors-based triple therapy. Upper, all eligible studies; middle, the subgroup compared to LPZ or EPZ; lower, the subgroup for Clarithromycin resistant strains

Subgroup Meta-Analysis

Subgroup 1 according to individual comparators

The results of the meta-analysis for subgroups stratified by individual comparators showed that the subgroups of LPZ or EPZ as comparators decreased heterogeneity (Fig. 3B): I2=0%, p=1.00 compared to EPZ by ITT; I2=0%, p=0.99 compared to LPZ by ITT; and I2=0%, p=0.74 compared to LPZ or EPZ by ITT. The subgroup of RPZ as a comparator increased heterogeneity (I2=79%, p=0.03 by ITT).

We also demonstrated that the VPZ-based therapy was more effective than the LPZ- or EPZ-based therapy: The RR for the eradication rate of the VPZ-based therapy as compared to that of the EPZ-based therapy was 1.11 (95% CI: 1.03-1.19, p=0.008); the RR for the eradication rate of the VPZ-based therapy as compared to that of the LPZ-based therapy was 1.20 (95% CI: 1.13-1.28, p<0.00001); the RR for eradication rate of the VPZ-based therapy as compared to that of the LPZ- or EPZ-based therapy was 1.16 (95% CI: 1.10-1.22, p<0.0001). Although the VPZ-based therapy was not inferior to the RPZ-based therapy, the difference was not statistically significant (RR: 0.84, 95% CI: 0.57-1.24, p=0.38 by ITT).

Subgroup 2 according to the study design

We analyzed the subgroups stratified by the study design (i.e., open-label and blind). The open-label subgroup reduced heterogeneity (I2=0%, p=0.99 by ITT), whereas the single-blind and double-blind subgroups increased heterogeneity (I2=54%, p=0.14 by ITT). We confirmed that the VPZ-based therapy was more effective than the PPI-based therapy in both the open-label and blind groups: in the open-label group, RR: 1.11 (95% CI: 1.03-1.19, p=0.004 by ITT); and in the blind group, RR: 1.26 (95% CI: 1.11-1.43, p=0.0003 by ITT).

Subgroup 3 according to the risk of bias in random sequence generation

We performed an analysis among studies stratified based on the risk of bias in random sequence generation. Except in one study, which was considered as having a high risk of bias, the four studies showed no heterogeneity by ITT (I2=0%, p=0.44).

Subgroup 4 according to CAM strains

When we stratified the studies according to the presence of CAM-resistant strains, the heterogeneity was decreased (Figure 3C): in CAM-resistant strains, I2=0%, p=0.78; and in CAM susceptible strains, I2=0%, p=0.47. The efficacy of eradication rate of VPZ-based therapy was significantly higher than the PPI-based therapy (RR for eradication rate: 1.29, 95% CI: 1.12-1.48, p<0.0003 by PP). In the subgroup of CAM-susceptible strains, the efficacy of eradication rates was not significantly different (RR for eradication rate: 1.01, 95% CI: 0.97-1.04, p=0.74 by PP).

Discussion

In this systematic review and meta-analysis, we combined the eradication rates reported in the included studies. We demonstrated that VPZ-based first-line triple therapy for H. pylori eradication was significantly more effective than the PPI-based therapy (RR for eradication rate: 1.17, 95% CI: 1.10-1.26, p<0.00001 by ITT). Especially, the VPZ-based therapy was more effective than the EPZ-based therapy or LPZ-based therapy (RR for eradication rate: 1.16, 95% CI: 1.10-1.22, p<0.00001 by ITT). We found that the VPZ-based therapy improved the H. pylori eradication rates, even in patients with CAM-resistant strains (RR for eradication rate: 1.29, 95% CI: 1.12-1.48, p=0.0003).

This review included two abstract-only reports compared to the previous meta-analysis study.30 Although the information on the baseline characteristics was limited, the result of our study supported the previous study that showed that the VPZ-based therapy was more effective than the PPI-based therapy (Odds ratio, 3.68 [1.87-7.26] p<0.05).30 VPZ is primarily metabolized by CYP3A4/5, and partially by CYP2B6, CYP2C19, and CYP2D6.41 According to Sugimoto et al., H. pylori eradication rates differ among patients with different CYP3A4/5 genotypes. The eradication rates in the CYP3A5*1 carriers were significantly lower than those in the CYP3A5*3/*3 carriers (72.7% vs. 90.7%, p=0.039).42 However, a recent study by Sugimoto et al. reported no significant differences in the eradication rates between the CYP3A4 and CYP2C19 gynotypes.43 PPIs are primarily metabolized by CYP2C19; however, whether the eradication rates are affected by the CYP2C19 genotypes varies with each PPI. A meta-analysis showed that the eradication rate of LPZ- and EPZ-based therapies was significantly dependent on the CYP2C19 genotypes, whereas that of the RPZ-based therapy was not.44 Although there may be a relationship between the eradication rates and genotypes, none of the included studies reported the efficacy of eradication by genotype. Given that genotypes influence the differences in eradication rates, more attention should be paid to genotype analyses in future studies.

Another factor related to the eradication rates is antibiotic resistance. A systematic review showed that the prevalence of primary CAM resistance in H. pylori is 10%, 18%, 10%, and 34% in the American, European, Southeast Asia, and Western Pacific regions, respectively.45 In cases wherein the incidence of CAM resistance has reached alarming levels worldwide and has an effect on the efficacy of treatment, it is highly beneficial to show higher eradication rates with VPZ-based therapy in patients with CAM-resistant strains than with PPI-based therapy. However, only two of the included studies analyzed the eradication rates according to CAM strains.

TPZ is mainly used for treating gastroesophageal reflux disease and gastritis in Korea. As a result of our systematic review, there was no RCT on H. pylori eradication for TPZ. However, a recent study on TPZ-based triple therapy was conducted in healthy volunteers.46 Further studies of the effect of TPZ on the patients with H. pylori infection would expect. Although it was not possible to determine whether the efficacy of H. pylori eradication was a PCAB class effect or a VPZ individual effect in this study, further studies including other PCABs should be performed in the near future.

This study had several limitations. First, although we tried to analyze the included RCTs as completely as possible, the number of studies and patients was small in some subgroups. Second, we included two abstract-only papers. The lack of detailed information makes it difficult to accurately evaluate their risk of bias. However, the RRs for all included and full-text studies were similar (1.22 vs. 1.17), so the effect of the publish type would have little on the result. Third, this study included only the result of the Japanese population even though it conducted a systematic search with no language restrictions. Therefore, comparing to other people and generalizing the efficacy of VPZ was limited. Finally, we focused only on the first-line triple therapy because it is the first step in eradication. Further studies on other regimens, such as VPZ-based second-line therapy or dual therapy with VPZ and AMX, are needed.

Conclusion

The H. pylori eradication rate was significantly higher with VPZ-based first-line triple therapy than with PPI-based first-line triple therapy. In particular, VPZ-based therapy showed a higher H. pylori eradication rate than the LPZ- or EPZ-based therapy and showed a better eradication rate than the PPI-based therapy, even in patients with CAM-resistant strains.

Supplemental Materials
yakhak-66-6-374-supple.pdf
Acknowledgment

This research was supported by a grant (21153MFDS601) from Ministry of Food and Drug Safety in 2022. We would like to thank Editage (www.editage.co.kr) for English language editing.

Conflict of Interest

All authors declare that they have no conflict of interest.

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