Vonoprazan and amoxicillin dual therapy versus bismuth-based therapy for Helicobacter pylori eradication: a systematic review and meta-analysis of randomized controlled trials

Abstract

Introduction

Helicobacter pylori infection can cause peptic ulcer disease, chronic gastritis, primary gastric lymphoma, and gastric cancer. Treatment with bismuth-based quadruple therapy is typically the first line of treatment but can be challenging due to increased pill burden and adverse effects, leading to nonadherence to therapy. Recent studies have shown that vonoprazan can be used in combination with amoxicillin as a potential treatment option. We conducted a systematic review and meta-analysis to assess the efficacy and tolerability of vonoprazan-based dual therapy as compared to bismuth-based therapy (BBT).

Methodology

We conducted a comprehensive search of multiple electronic databases including PubMed, Embase, and Cochrane Library to identify randomized controlled studies assessing vonoprazan and amoxicillin (VA) in comparison to BBT for H. pylori treatment in adults >18 years of age. Studies with pediatric populations, written in languages other than English, or without control groups were excluded.

Results

Out of the 1968 citations, 9 studies including 2039 patients were included in the final analysis. There were 463 and 481 men in the VA and the BBT groups, respectively. The mean age ranged from 38.1 to 48.7 years in the VA group and from 38.6 to 46.1 in the BBT group. The VA group had an eradication rate similar to that of the BBT group (odds ratio [OR]: 0.32, 95% confidence interval [CI]: 0.26–0.40; P = 0.08). The VA group had a lower incidence of total adverse events than the BBT group (OR: 0.32, 95% CI: 0.26–0.40; P = 0.0001), including a reduced occurrence of nausea and vomiting (OR: 0.42, 95% CI: 0.28–0.65; P = 0.0001). There was no difference in compliance between the VA and BBT groups (OR: 1.16, 95% CI: 0.76–1.76; P = 0.50).

Conclusion

Our study showed a similar eradication rate of H. pylori but a significantly lower incidence of adverse events in the VA group compared with the BBT group. Our analysis suggests that a VA-based regimen is an acceptable treatment option for H. pylori patients who cannot tolerate BBT.

Helicobacter pylori is a leading cause of peptic ulcer disease and can be associated with chronic gastritis, gastric cancer, and lymphoma, with an over 50% global prevalence.¹ In addition, H. pylori has been shown to have extragastric manifestations, e.g., in the central nervous system, as a trigger for autoimmune diseases, and cardiovascular disorders, and has been classified as a class I carcinogen by the World Health Organization.^2,3 Therefore, its eradication is paramount to reduce overall morbidity and mortality.⁴

Treatment strategies differ by geographic location, prevalence, bacterial resistance, cost of drugs, and availability. The American College of Gastroenterology recommends bismuth-based quadruple therapy (BQT) (bismuth, metronidazole, high-dose proton pump inhibitors [PPI], tetracycline) and clarithromycin-based triple therapy (PPI, amoxicillin, and clarithromycin) as the first-line treatment for H. pylori infection.⁵ The efficacy of clarithromycin-based triple therapy is limited by the widespread resistance to clarithromycin, and BQT is considered first-line therapy in regions with high clarithromycin resistance.⁶

BQT is composed of multiple drugs with a high pill burden, which can lead to adverse effects and gut microbiome dysbiosis. These adverse effects and the higher pill burden lead to low adherence rates.^4,5 This has led to research on dual therapy as a potential alternative.⁷ Previous studies reported similar eradication rates with fewer adverse effects with dual therapy composed of PPI and high-dose amoxicillin (2 g divided 3–4× per day) compared to BBT.^8,9

Vonoprazan, an H/K ATPase pump inhibitor, has a rapid onset of action, has fewer nocturnal acid breakthroughs, and is not affected by the CYP2C19 gene polymorphism when compared to PPI.^10,11 Vonoprazan has a higher 24-hour pH holding time ratio over high-dose PPIs, endorsing stronger potency.¹² We conducted a systematic review and meta-analysis to assess the efficacy and safety of vonoprazan-amoxicillin–based dual therapy (VA) as compared to bismuth-based regimens.

METHODS

The study was performed in compliance with Cochrane guidelines for conducting systematic reviews and meta-analyses and the Preferred Reporting Items for Systematic Reviews and Meta-analysis.^13,14 The study protocol was registered at PROSPERO with reference number CRD42023455492.

A literature search of multiple electronic databases (including Embase, Scopus, Web of Science, and Medline/PubMed) was conducted on October 15, 2024, using keywords [vonoprazan] AND [“H. pylori” OR “Helicobacter pylori”]. Two independent reviewers initially reviewed all articles for inclusion using titles and abstracts. In case of disagreements, a third reviewer reviewed the study for inclusion. Full-text manuscripts were reviewed for short-listed articles. The bibliographic section of the selected articles, as well as systematic and narrative articles on the topic, were manually searched for additional relevant articles.

We included randomized controlled clinical trials comparing VA dual therapy to BBT as a treatment for H. pylori infection in adults >18 years of age. We excluded studies performed in pediatric populations, as well as animal studies and studies in language other than English. We excluded abstracts, posters, letters to the editor, narrative reviews, comments, systematic reviews, meta-analyses, case reports, case series, and observational studies.

The primary outcome was the H. pylori eradication rate confirmed by a negative test 4 weeks or more after the end of the antimicrobial medication.¹⁵ Secondary outcomes were medication compliance, overall adverse events, diarrhea, dizziness, headache, skin rash, abdominal pain, and abdominal distension. Two independent coauthors extracted the data using a form, and a third coauthor verified the data prior to analysis. Review Manager 5.3 was used to run the analysis, and forest plots were generated. The Cochrane risk-of-bias tool for randomized trials, version 2, was utilized to assess the risk of bias and the quality of the studies (Table 1).¹⁶

Table 1.

Risk of bias assessment summary

Author name, year	Design	Tool used	Overall ROB
Chen, 202428	RCT	Cochrane RoB 2	Low
Hu, 202313	RCT	Cochrane RoB 2	Low
Huang, 202125	RCT	Cochrane RoB 2	High
Li, 202329	RCT	Cochrane RoB 2	High
Peng, 202314	RCT	Cochrane RoB 2	Low
Qian, 202317	RCT	Cochrane RoB 2	Low
Wang, 202230	RCT	Cochrane RoB 2	Low
Yan, 202028	RCT	Cochrane RoB 2	Low
Yang, 20198	RCT	Cochrane RoB 2	High

RCT indicates randomized controlled trial; ROB, risk of bias.

RESULTS

Out of 1968 citations, nine randomized clinical trials comparing the efficacy and safety of VA to BBT were included in this meta-analysis, as shown on the PRISMA flow chart (Figure 1).^15–17 A total of 2038 patients were included in the study. BBT included PPI, bismuth, and amoxicillin along with clarithromycin or metronidazole or furazolidone.^16,17 When quality assessment of included studies was assessed using the Cochrane ROB 2 tool, six studies had an overall low risk of bias, and three studies had an overall high risk of bias.

Figure 1.

PRISMA flow chart showing different stages of screening and number of studies included.

Eradication rate

The meta-analysis showed a similar H. pylori eradication rate in the VA group compared with the BBT group, with moderate levels of heterogeneity indicating nonsignificant variation in the outcomes (odds ratio [OR]: 1.44, 95% confidence interval [CI]: 0.96–2.14; I² = 56%) (Figure 2). With the exception of one sensitivity analysis with the study conducted by Yang et al, the VA group had a significantly higher eradication rate than the BBT group without a heterogeneity change in the results (OR: 1.64, 95% CI: 1.12–2.41; I² = 43%, P = 0.01) (Figure 3).

Figure 2.

H. pylori eradication rate in the vonoprazan and amoxicillin group compared to the bismuth-based therapy group.

Figure 3.

Leave-one-out sensitivity analysis comparing eradication of H. pylori in the vonoprazan and amoxicillin group compared to the bismuth-based therapy group.

Adverse events

The VA group had a lower incidence of overall adverse events than the BBT group (OR: 0.32, 95% CI: 0.26–0.40; I² = 0%) (Figure 4). The BBT group had a significantly higher rate of nausea and vomiting than the VA group with low heterogeneity between study results (OR: 0.42, 95% CI: 0.28–0.65; I² = 0%, P = 0.0001) (Figure 5). The BBT and VA groups had similar rates of dizziness and headache (OR: 0.56, 95% CI: 0.21–1.49; I² = 29%, P = 0.24), skin rash (OR: 0.77, 95% CI: 0.33–1.76; I² = 29%, P = 0.35), abdominal pain (OR: 0.83, 95% CI: 0.48–1.43; I² = 26%, P = 0.50), abdominal distension and early satiety (OR: 1.47, 95% CI: 0.32–6.67; I² = 38%, P = 0.62), and diarrhea (OR: 1.10, 95% CI: 0.65–1.84; I² = 29%, P = 0.73) (Supplemental Figures 1–5).

Figure 4.

Incidence of overall adverse events in the vonoprazan and amoxicillin group compared to the bismuth-based therapy group.

Figure 5.

Incidence of nausea and vomiting in the vonoprazan and amoxicillin group compared to the bismuth-based therapy group.

Compliance

There was no difference in compliance between the VA and BBT groups (OR: 1.16, 95% CI: 0.76–1.76; I² = 0%) (Figure 6).

Figure 6.

Compliance in the vonoprazan and amoxicillin group compared to the bismuth-based therapy group.

DISCUSSION

The effectiveness of H. pylori eradication therapies is declining, primarily due to antimicrobial resistance, with acid-suppressive drugs also playing a partial role.¹⁸ Studies have reported a general rise in primary resistance to H. pylori therapies, attributed to gene mutations, and incomplete adherence to therapy, leading to the need for newer treatment strategies.^19,20 Uses of multiple antibiotics are also limited by their side effects, including the effect on gut microbiota.^21,22

PPI and amoxicillin dual therapy is a reasonable strategy since amoxicillin has a low resistance rate and PPIs provide a nonacidic environment for higher amoxicillin efficacy.²³ However, the lack of American College of Gastroenterology adoption and lack of sufficient studies limit its widespread adoption.²⁴ In addition, a higher PPI and antibiotics dose in the therapy is required to improve efficacy and achieve desired eradication rates >90%.^8,25 Amoxicillin is pH dependent, and H. pylori is highly susceptible to amoxicillin at pH > 6; thus, it requires potent and sustained gastric acid suppression for eradication.²⁶ However, prolonged or higher-dose use of PPIs and antibiotics ultimately affects gut microbiota and leads to gastrointestinal disturbances.^21,23,25,27 Our meta-analysis showed that VA had similar rates of H. pylori eradication and offers an advantage of providing sustained and reliable acid suppression, since it is not subject to polymorphisms in CYP2C19

Adherence to H. pylori treatment is often impacted by adverse events, particularly nausea and vomiting, which are the most common side effects of eradication therapy. Our study found that the VA group experienced a lower overall rate of adverse events, including nausea and vomiting. This suggests that the VA regimen may be a preferable option for patients who have difficulty tolerating H. pylori treatment.

This study has several strengths, including a systematic literature search with well-defined inclusion and exclusion criteria and detailed data extraction. We included only randomized controlled trials, which leads to homogenous data and a decreased risk of bias compared with observational studies. Our meta-analysis has some limitations. First, all the included studies were based in China. Even though data were homogenous, the results may not be widely applicable. There was a paucity of literature from other parts of the world owing to costs and nonapproval. Second, the overall sample size was smaller; hence, the study may not have detected small differences. We could not evaluate the efficacy and safety of two therapies stratified by the dosages and regimen. Third, we could not consider the resistance pattern of the included populations, and antimicrobial susceptibility testing was not performed. Lastly, 24-hour intragastric pH was not monitored or considered and, hence, rates of “true acid suppression” are not known.

In conclusion, VA-based dual therapy is an acceptable treatment strategy, as evidenced by a similar H. pylori eradication rate and a lower adverse event rate in our study. VA therapy may have improved tolerability and, hence, overall patient satisfaction. Future multinational randomized controlled trials with larger sample sizes are required to find the optimal dosage, efficacy, and cost-effectiveness of VA-based therapy in different patient populations.

Disclosure statement/Funding

The authors report no funding or conflicts of interest.