Efficacy and Safety of 10‐Day Versus 14‐Day Bismuth‐Containing Quadruple Therapy for Helicobacter pylori Eradication: A Systematic Review and Meta‐Analysis

ABSTRACT

Background

Nearly half of the world population is infected by Helicobacter pylori ( H. pylori ). Bismuth‐containing quadruple therapy (BQT) has shown favorable outcomes. This study compares 10‐day and 14‐day BQT regimens to evaluate their efficacy, safety, and compliance rates.

Methods

We searched electronic databases from their inception until May 2024 to retrieve all randomized controlled trials (RCTs) that compared 10‐day and 14‐day BQT regimens for H. pylori eradication. Meta‐analysis was performed using Review Manager 5.4. Dichotomous outcomes were compared using the risk ratio (RR).

Results

Seven RCTs and a total of 2424 patients were included in the meta‐analysis. There was no significant difference in the intention‐to‐treat eradication rate (RR 0.97; 95% CI 0.94, 1.01) and the per‐protocol eradication rate (RR 0.96; 95% CI 0.93, 1.00) between the 10‐day BQT and 14‐day BQT groups. Commonly reported adverse events in both groups were epigastric pain and discomfort, nausea, and vomiting. There was no significant difference in the risk of adverse events between the two groups (RR 0.85; 95% CI 0.70, 1.03). There was no significant difference in the compliance rate between the two groups (RR 1.02; 95% CI 1.00, 1.04).

Conclusion

The eradication rates, risk of adverse events, and compliance rates were comparable between the two groups. Future research comparing similar drug doses with larger sample sizes and longer patient follow‐ups can improve the quality of results.

Abbreviations

BQT

Bismuth‐containing quadruple therapy

ITT

intention‐to‐treat

PP

per protocol

UBT

urea breath test

1. Introduction

A significant proportion of the world's population is afflicted by Helicobacter pylori ( H. pylori ) infection. In 2015, around 4.4 billion people worldwide were reportedly impacted by this infection [1]. The burden of H. pylori infection is higher in developing countries than in developed countries, with the highest prevalence in African and Eastern Mediterranean regions. The adult population is affected by H. pylori infection more than children and adolescents, with a prevalence rates of 43.9% and 35.1%, respectively [2]. H. pylori is recognized as the causative agent of various gastrointestinal conditions, including chronic gastritis, peptic ulcers, and gastric mucosa‐associated lymphoid tissue (MALT) lymphoma [3, 4].

Untreated H. pylori infection can result in accelerated loss of specialized glands in the stomach, leading to atrophic gastritis and increasing the risk of gastric carcinoma. Seeking timely effective treatment is crucial in preventing detrimental outcomes [5]. Elimination of infection is cost‐effective, especially for high‐risk individuals. The treatment costs in patients with successful eradication were found to be almost half those accrued by the individuals with treatment failure and associated complications [6].

Triple or quadruple therapy is the two commonly employed regimens for eradicating infection. Triple therapy includes a combination of a proton pump inhibitor (PPI) and two antibiotics, such as amoxicillin and clarithromycin or metronidazole. The efficacy of triple therapy is declining due to antibiotic resistance [7]. Quadruple therapy, which consists of adding bismuth to the triple therapy, is effective in areas with high antibiotic resistance [8]. In a meta‐analysis, it was found that quadruple therapy has better cure rates than triple therapy [9].

The duration of bismuth quadruple therapy is still under evaluation. The previous systematic review and meta‐analysis comparing the two treatment regimens exhibited comparable eradication rates, with a lower risk of adverse events in the 10‐day bismuth‐containing quadruple therapy (BQT) group. However, since the previous meta‐analysis, three RCTs [10, 11, 12] have been published that have conflicting outcomes with one another and have not been incorporated into a meta‐analysis, with one being the largest trial comparing the two regimens to date [10]. The new studies collectively comprise a sample size greater than that of the previous meta‐analysis. A shorter duration of therapy can improve patient compliance, with potential savings in healthcare expenses and fewer drug shortage concerns.

This meta‐analysis aimed to assess the effectiveness of the 10‐day BQT compared to the 14‐day BQT and to profile the adverse events associated with both treatment durations.

2. Materials and Methods

This systematic review was conducted according to the methodological guidelines outlined in the Cochrane Handbook for Systematic Reviews of Interventions. The reporting follows the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement [13]. The review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the identifier CRD42024551033. Ethical approval was not required for this study.

2.1. Eligibility Criteria

The inclusion criteria were as follows: (1) Study design: RCTs; (2) Population: adults over 18 years of age, undergoing medical therapy for H. pylori eradication; (3) Intervention: 10‐day BQT therapy (quadruple therapy was defined as a combination of three medications including a PPI, and two antibiotics with any formulation of bismuth); (4) Comparator: 14‐day BQT therapy; (5) outcomes: reporting any outcome of interest.

The exclusion criteria were: (1) Study designs other than RCTs, such as case series and case reports, quasi‐randomized trials, and observational studies; (2) Treatment regimens other than 10 and 14‐day BQT; (3) treatment regimens not having bismuth in them; (4) studies conducted on animals; and (5) studies in languages other than English.

2.2. Information Sources

A comprehensive search strategy was employed to identify relevant studies. We searched electronic databases and international trial registries from inception to May 2024. The search was conducted using the Cochrane Central Register of Controlled Trials (via The Cochrane Library), MEDLINE (via PubMed), Embase (via Ovid), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (ICTRP) portal. No language restrictions were applied. Additionally, gray literature sources such as ProQuest Dissertations & Theses Global and OpenGrey were explored for potentially relevant data. Reference lists of included articles and relevant systematic reviews were hand‐searched to identify further eligible studies. Forward citation tracking was conducted using the Web of Science to retrieve any additional pertinent research. A detailed search strategy utilizing keywords and Medical Subject Headings (MeSH) terms related to 10 and 14‐day bismuth‐containing quadruple therapy, H. pylori , and eradication is provided in Table S1.

2.3. Selection Process

A two‐stage screening process was employed for article selection. All retrieved citations were uploaded to Rayyan AI, a web‐based platform for systematic reviews. Two authors independently screened titles and abstracts against pre‐defined eligibility criteria. Next, full‐text articles of potentially eligible studies were retrieved and independently reviewed by the same authors. Disagreements were resolved through arbitration by a senior author.

2.4. Data Collection Process and Data Items

After the process of study selection, data were extracted by two reviewers into a pre‐piloted Microsoft Excel spreadsheet to ensure consistency of data extraction. Relevant data items were extracted, including patient characteristics (number of participants, their mean age in years, percentage of male population, confirmatory diagnosis for H. pylori infection, treatment‐naive population), intervention details (including study arms and regimen), comparator details (14‐day BQT regimen), study characteristics (trial name, first author, year of publication, name of country in which the study was conducted, duration of follow‐up), and the outcome variables. Our primary outcomes were the intention‐to‐treat eradication rate and the per‐protocol eradication rate. The intention‐to‐treat analysis (ITT) includes all participants who were randomized at the beginning of the study, irrespective of whether they completed the prescribed treatment or follow‐up. Per‐protocol (PP) only considers those participants in the analysis who completed the therapy as described in the protocol, without any major violations. We analyzed the eradication rates by creating two subgroups: one for studies in which the participants received bismuth‐metronidazole‐tetracycline (BMT) based bismuth‐containing quadruple therapy and another subgroup for those studies that employed other regimens for treatment. Secondary outcomes included the incidence of adverse events and the compliance rate.

2.5. Risk of Bias Assessment

Two authors assessed the risk of bias in the included studies using the revised Cochrane Risk of Bias tool for randomized trials (RoB 2.0) [14], which assesses bias in the following 5 domains: (1) Bias arising from the randomization process; (2) Bias caused by deviations from intended interventions; (3) Bias caused by missing outcome data; (4) Bias in the measurement of the outcome; and (5) Bias in the selection of the reported result. Two authors independently rated the risk of bias for each included study as low, high, or some concerns. A third author resolved any disagreement between them.

2.6. Data Synthesis

We used review manager (RevMan, version 5.4; The Cochrane Collaboration, Copenhagen, Denmark) for statistical analysis. Dichotomous outcomes were reported as relative risk (RR) with 95% confidence intervals (CIs). The random‐effects model with the Mantel–Haenszel method was used to perform meta‐analyses. A two‐tailed p‐value less than 0.05 was taken to be significant.

For each synthesis, the I² index and the chi‐square test were used for the assessment of heterogeneity, and a p‐value of < 0.1 was considered significant for the heterogeneity of the included studies.

3. Results

The study selection process is illustrated in the PRISMA flowchart in Figure 1. An initial search yielded 309 studies. After removing duplicates, screening titles, and abstracts, the studies were assessed by their full‐text manuscripts. Subsequently, seven RCTs were included in the analyses.

FIGURE 1.

PRISMA flowchart for selection of studies.

Table 1 summarizes the main characteristics of all included studies, such as age, country, and treatment drugs. Seven RCTs [10, 11, 12, 15, 16, 17, 18] of BQT were analyzed to compare the eradication rates of treatment durations of 10 and 14 days. All studies reported both ITT and PP eradication rates for the specified treatment durations. Additionally, one of the studies [17] had two pairs of intervention and control groups (10‐day and 14‐day bismuth‐quadruple therapies and moxifloxacin‐bismuth combined therapies), which were pooled separately in the meta‐analysis. The studies also reported the overall incidence of adverse effects and patient compliance. In the trials, 2424 patients were assigned to either the 10‐day duration group (n = 1223) or the 14‐day duration group (n = 1201). The trials were conducted in China (4 trials), Italy, Turkey, and Taiwan. All trials enrolled treatment‐naïve patients. Confirmation of H. pylori diagnosis was made by 13‐C Urea breath test (13C‐UBT), gastric biopsy and histology, and tissue culture. Detailed study characteristics are provided in the Table S2.

TABLE 1.

Study characteristics of the included studies.

Study ID	Location	Included study arms	Included participants	Mean age ± SD in years	Male %	Duration of follow‐up
Chen et al. [15]	China	10‐day versus 14‐day Rabeprazole BQT	120 versus 120	45.89 ± 12.92 versus 48.11 ± 12.39	56.7 versus 50.8	4 weeks
Dore et al. [16]	Italy	10‐day versus 14‐day Bismuth, Tetracycline, Metronidazole, and Esomeprazole	215 versus 202	52 versus 53	37.7 versus 35.6	4–6 weeks
Etik et al. [17]	Turkey	10‐day versus 14‐day bismuth‐containing quadruple treatment group (10‐BQT vs. 14‐BQT groups) 10‐day versus 14‐day moxifloxacin‐bismuth combined treatment groups (10‐MBCT vs. 14‐MBCT groups)	54 versus 54 54 versus 54	40 ± 11.0 versus 44 ± 12.5 41 ± 11.5 versus 43 ± 11.5	31.5 versus 35.2 40.7 versus 42.6	6–12 weeks
He et al. [12]	China	10‐day versus 14‐day Antofloxacin containing BQT (ANT10 vs. ANT14)	395 versus 387	43.0 ± 11.8 versus 44.2 ± 11.1	51.6 versus 55.3	6 weeks
Lu et al. [11]	China	10‐day versus 14‐day Vonoprazan BQT	78 versus 78	37.1 ± 19.7 versus 35.9 ± 11.5	41.0 versus 47.4	6–8 weeks
Niu and Bai et al. [18]	China	10‐day versus 14‐day Ilaprazole, Amoxicillin. Furazolidone, Bismuth Glycyrrhizinate (10‐IAFB vs. 14‐IAFB)	150 versus 150	44.25 ± 12.67 versus 44.10 ± 13.90	45.5 versus 42.1	4–6 weeks
Yang et al. [12]	Taiwan	10‐day versus 14‐day Bismuth Quadruple Therapy (10‐BQT vs. 14‐BQT)	157 versus 156	55.0 ± 14.6 versus 55.0 ± 13.0	52.9 versus 42.9	At least 4 weeks

3.1. Risk of Bias Assessment

One study exhibited a low risk of bias, while there were some concerns of bias in the other six studies. These concerns mainly arose due to issues in the randomization process (two studies) and the selection of reported results (four studies). Additionally, one study had a considerable loss of population to follow up. The details of the bias assessment are provided in the Table S3.

3.2. Results of the Meta‐Analysis

3.2.1. Eradication Rate

Seven studies reported data on the eradication rate. For the ITT analysis, the eradication rate for the 10‐day group was 86.6%, while that for the 14‐day group was 90.3%. There was no significant difference between the two treatment groups (RR 0.97; 95% CI 0.94, 1.01; p‐value = 0.12; I² = 38%). Additionally, neither subgroup analysis (BMT‐based quadruple therapy and non‐BMT regimen) showed significant differences in eradication rate between the 10‐day and 14‐day groups (Figure 2). In the PP analysis, the eradication rates were 90.8% and 96.0% in the 10‐day and the 14‐day groups, respectively; there was no statistically significant difference in the eradication rates of the 10‐day and the 14‐day groups (RR 0.96; 95% CI 0.93, 1.00; p‐value = 0.05; I² = 75) in the PP analysis. Similar to the intention‐to‐treat analysis, no significant difference was observed in the two subgroups (Figure 3). Additionally, the eradication rate in the 10‐day group receiving BMT was greater than that of those receiving the non‐BMT therapy (ITT analysis: 91.6% vs. 83.9%; PP analysis: 95.8% vs. 88.2%).

FIGURE 2.

Forest plot for eradication (Intention‐to‐treat analysis) with subgroup analysis comparing bismuth‐metronidazole‐tetracycline (BMT) based BQT and non‐BMT regimens.

FIGURE 3.

Forest plot for eradication rate (Per‐protocol analysis) with subgroup analysis comparing bismuth‐metronidazole‐tetracycline (BMT) based BQT and non‐BMT regimens.

3.2.2. Adverse Effects

All the included studies mentioned details regarding the adverse effects, with gastrointestinal symptoms being the most prominent ones. The rate of adverse events was comparable between the two groups, with 18.6% of the participants in the 10‐day BQT group and 21.7% of the participants in the 14‐day BQT group developing an adverse event. The risk of adverse events was not significantly different between the two groups (RR 0.85; 95% CI 0.70, 1.03; p‐value = 0.09; I ² = 25%) (Figure 4). The studies demonstrated no significant heterogeneity while assessing adverse events.

FIGURE 4.

Forest plot for adverse events.

The adverse effects most commonly reported by studies were epigastric discomfort and pain, nausea, and vomiting. Additionally, the study by Yang et al. reported a significantly lower incidence of dizziness and vomiting in the 10‐day group compared to the 14‐day group [12].

3.2.3. Compliance

The compliance rate was reported by five studies included in the analysis. The compliance rate in the 10‐day group was 94.6%, compared to 93.0% in the 14‐day group. There was no significant difference in the compliance rate between the study groups (RR 1.02; 95% CI 1.00, 1.04; p‐value = 0.14; I² = 0%) (Figure 5). There was no significant heterogeneity observed in the studies assessing compliance rate.

FIGURE 5.

Forest plot for compliance rate.

4. Discussion

In this meta‐analysis, which included data from 7 RCTs, we evaluated the efficacy and safety of two treatment regimens for treatment‐naive H. pylori ‐infected individuals: a 10‐day BQT and a 14‐day BQT. The analysis included 2424 patients and concluded that there was no significant difference in eradication rates between the two groups. Furthermore, the risks of adverse events and compliance rates were comparable between the two treatment durations. These findings suggest that both regimens are equally effective and safe for treating H. pylori infections, providing flexibility in treatment duration without compromising the efficacy or safety. The risk of bias in the studies included in this review was mostly moderate, with one study having a low risk of bias.

Our findings align with previous studies showing no significant difference in eradication rates between 10‐day and 14‐day BQT regimens for H. pylori . However, the previous meta‐analysis assessing the two treatment regimens exhibited a statistically significant difference in the risk of adverse events, with the 10‐day group having fewer adverse reactions [19]. This was not concordant with our meta‐analysis, as the two groups demonstrated no significant difference in the risk of adverse events. This is further backed by the latest trials by He et al., Lu et al., and Yang et al. that showed a comparable risk of adverse events between the two groups [10, 11, 12]. This difference can be explained by the observation that meta‐analyses involving studies with small sample sizes may provide significant results that are not substantiated by subsequent larger trials [20].

Among the included studies, the trial by He et al. showed significant improvement in eradication rates in the 14‐day BQT group over the 10‐day BQT group in both the ITT and PP analysis. This study was also the largest trial to date comparing the two therapies. Drug resistances were reported by two of the studies included in our review. In the study by Niu et al., the single‐drug resistance rates of H. pylori to clarithromycin, levofloxacin, and metronidazole were reportedly high—75.0%, 81.3%, and 93.8%, respectively. Minimal resistance was reported against amoxicillin and tetracycline [18]. In the study by He et al. 2022, the overall drug resistance rate of H. pylori strains was 57.0% of the total strains; the single drug resistance rate was 48.6%—352 out of 724 strains were resistant to at least one drug. This was highest for clarithromycin (39.8%). Multidrug resistance was low, and virtually no strains were reported to be resistant to all three antibiotics. This study also demonstrated that drug resistance significantly reduced the odds of H. pylori eradication. The 10‐day therapy group had a significantly lower eradication rate than the 14‐day therapy group for antibiotic‐resistant strains [10]. Niu et al. demonstrated that the greatest incidence of resistance occurred against clarithromycin, metronidazole, and levofloxacin. Additionally, they demonstrated fewer costs incurred by patients on 10‐day therapy compared to 14‐day therapy [18]. Recent trials have also shown greater cost‐effectiveness of the shorter‐duration therapy compared to the longer‐duration regimen [11].

Current guidelines advocate for the triple as well as bismuth‐containing quadruple regimens. While the World Gastroenterology Organization (WGO) recommends a 7‐day BQT, 10‐day and 14‐day regimens are also widely recognized and used, especially in areas of higher antibiotic resistance [21]. The 10‐day commercial preparations of BMT therapy (Pylera) with proton‐pump inhibitors or potassium‐competitive acid blockers have shown promise as first‐line therapy; their use as an alternative therapy in patients resistant to other regimens has shown limited efficacy [22, 23]. The use of 14‐day BMT as optimized BQT for treatment‐naïve patients as well as those exhibiting resistance to clarithromycin and levofloxacin‐based therapies has recently been incorporated into the guidelines of the American College of Gastroenterology [24]. Clarithromycin‐based therapies are only recommended when the resistance rates are below 15% and should be abandoned when the resistance rate reaches 15%–20% [25]. While metronidazole and tetracycline are the most preferred antibiotics, the addition of bismuth to standard triple therapy containing clarithromycin has shown favorable results [26]. There is current evidence to support that the 7‐day therapy may not be inferior to 14‐day therapy against antibiotic‐resistant strains [27]. Further investigation into the treatment of drug‐resistant strains is still required.

The previous meta‐analysis was significantly limited by the small sample size and low power of the results. Additionally, the fixed effects model of statistical analysis was used despite significant heterogeneity in the included studies concerning the individual regimens, populations, and sample sizes. The fixed effects model tends to give greater weight to studies with larger sample sizes, thus undermining the effects of small sample size studies [28]. Also, it is not reasonable to assume that the intervention effects across all studies are identical, as the analysis demonstrates differences in the individual study effects [29]. We believe the sample sizes and interventional effects between the studies are adequately different; hence, a random effects model should be used. Significant antibiotic resistance was reported in one of the studies within the region being studied [16, 30]. This can hinder the comparability of results across studies, as other studies did not report similar resistance in their regions. Moreover, the study by Etik Ozer et al. reported two different pairs of 10‐day and 14‐day BQT, which were pooled together into a single intervention and control group [17]. Our study assessed the two pairs separately.

Our study includes data from seven RCTs, providing a robust sample size and enhancing the reliability of the results. Moreover, by focusing on treatment‐naive individuals, the study ensures that the results are not influenced by prior treatments and associated antibiotic resistance. Incorporating the latest RCTs, our study provides up‐to‐date evidence, reflecting the most recent clinical practices and findings in the treatment of H. pylori .

The non‐inferiority of the 10‐day BQT group demonstrated by our study also has logistical benefits. It reduces the wastage of drugs required for disease treatment while also reducing out‐of‐pocket costs for patients who would have to pay more for the longer duration of therapy [31]. This becomes even more important in the context of developing countries, which face medication shortages on a larger scale [32].

Clinicians may prescribe either the 10‐day or 14‐day BQT regimen, with knowledge of both treatments having comparable efficacy. This flexibility allows personalized treatment plans tailored to individual patient needs and circumstances. With no significant difference in outcomes, healthcare providers can optimize resource use by selecting the most appropriate regimen based on factors such as cost, availability, and patient preference without compromising treatment success. Our findings highlight the need for continued research on long‐term outcomes and recurrence rates.

Another cost‐effective method with a high eradication rate is sequential therapy, which has only recently been used in the context of quadruple therapy. It offers a high eradication rate with significant cost‐effectiveness, which should be investigated further in large sample‐size RCTs [33, 34].

5. Limitations

This study has some limitations, mainly the lack of longer follow‐up times, which hinders the assessment of re‐infection or long‐term adverse events. Most of the studies had biases related to the randomization process (mainly the concealment of allocation) or selection bias. All the trials were single‐center studies (except Yang et al. and Chen et al.), and such studies have limited external validity of the results and may overestimate the effect of the intervention [35, 36].

6. Conclusion

Our meta‐analysis comparing the 10‐day and 14‐day BQT regimens for treatment‐naive H. pylori infections found no significant difference in eradication rates, compliance, or incidence of adverse events between the two treatment durations. These findings suggest that both regimens are equally effective and safe for H. pylori eradication, providing flexibility in treatment choices based on patient preferences, logistical constraints, and clinical circumstances.

Disclosure

The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1. Supporting Information.

Table S1. Detailed search strategy and results.

Table S2. Detailed study characteristics (b.i.d. = Twice daily dose, t.i.d. = Three times a day).

Table S3. Detail of risk of bias assessment.