INTRODUCTION
Helicobacter pylori H. pylori ) has been recognized as a major human pathogen for nearly four decades. Furthermore, it remains the most common human bacterial pathogen, infecting approximately half of the world’s population.[ 1 ] Worldwide, the infection rate of H. pylori varies by geographic region, but the number of infected people has persisted or even increased over the past three decades due to population growth and re-infection, and relapse caused by unsuccessful eradication .[ 2 ] 25% ~ 30% of H. Pylori infected patients will appear in different degrees of gastrointestinal diseases, such as dyspepsia, chronic gastritis, peptic ulcer, gastric cancer, etc., H. Pylori infection has also been associated with multiple extra-gastrointestinal diseases, such as iron deficiency anemia, idiopathic thrombocytopenic purpura, autoimmune disease, and cardiovascular diseases.[ 3 ] As a result, many therapeutic options have been explored to eradicate H. pylori . After years of exploration, bismuth-containing quadruple therapy (BQT), including proton pump inhibitors (PPI), bismuth, and two antibiotics, has become the current first-line treatment in practice guidelines in many countries.[ 1 , 3 , 4 ]
However, the BQT regimen cannot fully meet clinical needs due to a large number of adverse events . High-dose dual therapy (HDDT), including PPI and amoxicillin, has been reported in recent years, although the results have been controversial. For example, Suo et al .[ 5 ] reported that dual therapy with rabeprazole and amoxicillin could achieve favorable efficacy, safety, and compliance in the first-line eradication of H. pylori infection. While Kwack W et al .[ 6 ] suggested that high-dose ilaprazole plus amoxicillin was ineffective as the first-line therapy for eradicating H. pylori in Korea. Meanwhile, inconsistent results were also found in the comparative study of HDDT and BQT. For instance, Hu et al .[ 7 ] concluded that HDDT could achieve a comparably higher eradication rate than BQT, while Bacaksız et al .[ 8 ] showed that HDDT embraced a low eradication rate compared with BQT. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety of HDDT versus BQT in eradicating H. pylori .
MATERIALS AND METHODS
Search strategy
This meta-analysis was conducted according to the reporting guidelines of the PRISMA protocol.[ 9 ] The protocol of this study is documented on PROSPERO (CRD42022360612). Two independent researchers (Chong Zhang and Yu-jie Cheng) searched PubMed, Embase, and Cochrane Library from 2002 to August 31, 2022 (last 20 years). The following search terms were used: (“Helicobacter pylori ” OR “H. pylori ” OR “Campylobacter pylori”) AND ((“Dual therapy”) OR (“bismuth” AND “quadruple therapy”)).
Selection criteria
Inclusion criteria: 1) Comparative studies on evaluating HDDT (PPI and amoxicillin both were administered 3 or 4 times a day and amoxicillin ≥ 2.0 g/day) versus BQT (PPI, Bismuth, and 2 antibiotics which was not limited to metronidazole and tetracycline because of a large number of expansion regimens in Asian countries) in terms of H. pylori infection; 2) The study design was a randomized controlled trial (RCT); 3) Participants did not receive previous eradication treatment for H. pylori; 4) Duration of treatments in HDDT was 14 days while it should be 10~14 days in BQT according to the treatment guidelines.[ 1 , 3 , 4 ]
Exclusion criteria: 1)Animal studies, case reports or case series, retrospective studies, cohort studies, and non-control studies or studies with an inappropriate control group; 2) Duplicated publications or overlapping data; 3) Editorials, comments, meta-analysis, and reviews; 4) Use of traditional Chinese medicine or probiotics.
Data extraction
Two authors (Chong Zhang and Yu-jie Cheng) independently extracted data and resolved the disagreements through group discussion or consultation with the third independent author (Jun Zhang). The following data were collected: 1)Characteristics of the selected studies, including the first author, the year of publication, the countries or regions where the study was conducted, the study design, the characteristics of participants, the diagnostic approach of H. pylori infection, confirmative test for eradication , and the time to confirm the eradication of H. pylori ; 2)Therapeutic regimens, duration of treatment, number of patients in each group; 3) The eradication rate by intention-to-treat (ITT) analysis and per-protocol (PP) analysis, the compliance of patients and number of patients with adverse events .
Outcome assessment and risk of bias
The primary outcome was the eradication rate of HDDT and BQT, including ITT and PP analysis. The secondary outcomes were the incidence of adverse events and compliance of patients in both groups.
According to the Cochrane Handbook for Systematic Reviews of Interventions,[ 10 ] the risk of bias in each of the included studies was evaluated by two independent authors (Chong Zhang and Yu-jie Cheng). The risk of the bias components was scored as follows: low risk, high risk, or uncertain bias risk.
Statistical analysis
The meta-analysis was conducted through RevMan software version 5.4.1 (Nordic Cochrane Centre, Copenhagen, Denmark). Dichotomous outcomes were determined using the Mantel-Haenszel method and summarized as the risk ratio (RR) with a 95% confidence interval (CI). P < 0.05 was considered statistically significant. The heterogeneity of the included studies was evaluated by performing χ2 tests (assessing the P value) and by calculating the inconsistency index (I 2 ) statistic.[ 11 , 12 ] If the P value was less than 0.10 and I 2 exceeded 50%, heterogeneity was considered to be substantial. A fixed effects model was used if I 2 ≤50%, otherwise a random-effects model was applied.
The publication bias was preliminarily estimated using a funnel plot, which is constructed by RevMan software. Furthermore, Egger’s test was performed using Stata version 12.0 (Stata Corp LP, College Station, TX, USA),[ 13 ] so as to accurately evaluate the publication bias. P < 0.05 was considered statistically significant. If the publication bias was evidenced, a trim and fill analysis was conducted, which yielded an effect adjusted for funnel plot asymmetry.[ 14 ]
RESULTS
Study selection
A total of 1318 studies were obtained from the database, including 235 studies from Pubmed, 361 studies from Embase, and 722 studies from Cochrane Library. Seven hundred and seventy one studies were removed because of duplication. Then, 332 studies were excluded because they were irrelevant to the current analysis. Furthermore, 127 records including animal studies, case reports or case series, retrospective studies, cohort studies, and non-control studies were excluded after retrieving the abstract. In the last step, 74 studies were excluded because the control group was inappropriate, the treatment experience was not naïve, or the key content was not clearly described. Finally, 5604 participants from14 RCTs were enrolled in this meta-analysis [Figure 1 ]. Noteworthy, 3 studies[ 7 , 15 , 16 ] were not included because the patients were not treatment-naive while another study[ 8 ] was not included because the therapeutic regimen was unclear, and the results were not distinguished by ITT and PP analysis.
Figure 1: Flowchart of literature selection
Characteristics of the selected studies
The characteristics of the included studies are shown in Table 1 . Of the 14 studies, 9[ 17-25 ] were conducted in mainland China, 3[ 26-28 ] in Taiwan province of China, 1[ 29 ] in Colombia and 1[ 30 ] in Turkey. The age of participants was more than 18 years except for the study by Niu (14~70 years old).[ 18 ] Test for diagnosing H. pylori including 13 C or 14 C- urea breath test (UBT), histological examination (HE), rapid urease test (RUT), and biopsy culture. While the test for confirming eradication included 13 C or 14 C-UBT, and stool H. pylori antigen test. Of the 14 included trials, 11[ 17-25 , 29 , 30 ] were published as full-length articles, whereas 3[ 26-28 ] were conference abstracts.
Table 1: The characteristics of the included studies
Risk of bias in included studies
The potential bias of each study was assessed through several aspects, including selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases, as shown in Supplementary Figure 1
Eradication rateIn ITT analysis, the overall eradication rates of H. pylori were evaluated in all 14 studies, with the rate of 87.46% (2497/2855) in the HDDT group and 85.70% (2356/2749) in the BQT group. Due to non-significant heterogeneity (I 2 = 39%, P = 0.07), the fixed effects model was used, and there was a significantly bordered difference between the two groups (RR = 1.02, 95% CI: 1.00 ~ 1.04, P = 0. 03) [Figure 2a ].
Figure 2: Forest plot of Helicobacter pylori eradication rate (a, intention-to-treat analysis; b, per-protocol analysis). CI: confidence interval; HDDT: High Dose Dual Therapy; BQT: Bismuth-Containing Quadruple Therapy ; M-H: medium to high
For the overall eradication rates of PP analysis, 13 studies were included (lack of data in one study[ 26 ] ), with the eradication rate of 89.97% (2206/2452) in the HDDT group and 89.82% (2064/2298) in the BQT group. Using a fixed effects model for analysis (Heterogeneity analysis: I 2 = 35%, P = 0.10), no significant difference was found (RR = 1.00, 95% CI: 0.99~1.02, P = 0.67) [Figure 2b ].
Adverse effects
For adverse effects, 12 studies (two studies had no data[ 26 , 30 ] ) were included for adverse effects analysis using the random effects model I2 = 60%, P < 0.1. As per the results, the overall treatment-related events in the HDDT group (13.00%, 312/2400) were significantly less frequent than that in the BQT group (31.05%, 716/2306), with RR = 0.41 (95% CI: 0.33~0.50, P < 0.00001) [Figure 3 ].
Figure 3: Forest plot of the adverse effects. CI: confidence interval; HDDT: High Dose Dual Therapy; BQT: Bismuth-Containing Quadruple Therapy ; M-H: medium to high
Compliance
For compliance analysis, 9 studies were included (5 studies had no data[ 24 , 26-29 ] ). In 8 studies, compliance was defined as good when participants took more than 80% of the total medication,[ 17-23 , 25 ] while in another study, the standard was 95%.[ 30 ] As a result, good compliance rate in the HDDT group (95.88%, 1885/1966) had no significant difference compared with the BQT group (93.84%, 1737/1851), with RR = 1.01 (95% CI: 1.00~1.03, P = 0.14) [Figure 4 ].
Figure 4: Forest plot of the compliance. CI: confidence interval; HDDT: High Dose Dual Therapy; BQT: Bismuth-Containing Quadruple Therapy ; M-H: medium to high
Risk of bias
To control the publication bias, Egger’s test was performed for the eradication rate, adverse events , and compliance [Supplementary Figure 2 eradication rate of ITT analysis was P = 0.07, the eradication rate of PP analysis was P = 0.08, the adverse events analysis was P = 0.01 and compliance analysis was P = 0.10, indicating that there was a significant publication bias in the adverse events analysis.
In order to obtain the adjusted result, the trim and fill analysis was conducted for adverse events analysis. As a result of the eradication rate, 5 virtual studies were added with pooled data of RR = 0.49 (95% CI: 0.44 ~ 0.55, P < 0.00001), indicating an unchanged tendency [Figure 5 ].
Figure 5: Funnel plot of adverse events (trim and fill analysis)
DISCUSSION
The eradication rate is the first indicator to be considered in the treatment of H. pylori infection. However, as the incidence of antibiotic resistance increases, the chance of eradication failure also increases. In the Western Pacific region, the antibiotic resistance rate of clarithromycin, metronidazole, and levofloxacin is about 34%, 55%, and 24%, respectively, while the antibiotic resistance rate of amoxicillin was only 1%. Similar phenomena can also be seen in other regions, such as Southeast Asia and Europe.[ 1 ] Therefore, theoretically, higher doses of amoxicillin can provide superior effects, which may be one of the important reasons for HDDT research in recent years. From the perspective of pharmacokinetics, amoxicillin is a kind of time-dependent drug, and the plasma concentration can be maintained above the minimum inhibitory concentration for 6-8 hours, which means that the plasma concentrations of amoxicillin cannot be achieved by the traditional administration of 1 g twice daily.[ 31 ] Therefore, more frequent dosing regimens may yield better efficacy. In this meta-analysis, although there was only one antibiotic in HDDT, the eradication rate was similar to that of BQT in PP analysis. Inconsistently, a bordered significant difference was found in ITT analysis. We believe that different numbers of participants lost to follow-up may account for the gap between ITT and PP analysis results.
In terms of adverse effects, BQT requires the continuous use of a bismuth agent and two antibiotics, which increases the patient’s antibiotic load, leading to more adverse events . In this meta-analysis, the associated adverse reactions included bitter taste, diarrhea, abdominal distension, dry mouth, nausea, abdominal pain, loss of appetite, belching, bad breath, vomiting, acid regurgitation, constipation, insomnia, fatigue, dizziness, headache, blackened tongue coating, swallowing discomfort, etc., We found that the adverse events rate in the HDDT group was 13.0%, which was significantly less frequent than that in the BQT group. Notably, 2 studies[ 26 , 30 ] were excluded from 14 RCTs due to the absence of adverse events data. Moreover, we found significant publication bias, and we believe it is due to some small sample studies, such as the outlier from the study by Yun, et al .[ 21 ] However, the tendency was unchanged when we adjust the data by trim and fill analysis. More adverse events lead to more participants lost to follow-up, which can decrease the eradication rate by ITT analysis in the BQT group. This result is consistent with the difference between the ITT and PP analysis of the eradication rate.
Compliance is another issue we focused on due to its close association with efficacy. Unfortunately, only 9 studies[ 17-23 , 25 , 30 ] showed their data in this meta-analysis. As a result, the good compliance rate in the HDDT group was higher than that in the BQT group but had no significant difference. The reason may be that there are fewer types of drugs and fewer adverse reactions in the HDDT regimen, which is consistent with data on the incidence of adverse events , but there was insufficient data for analysis. However, due to different criteria of good compliance (8 studies[ 17-23 , 25 ] defined as participants taking more than 80% of the total medication, while another study[ 30 ] defined it as 95%), the final results may be slightly skewed. In addition, no publication bias was found despite our cautious assessment. Therefore, the result was considered to be generally credible.
In terms of the inadequacies of this paper, some related research, such as the retrospective studies, were not included, which may lead to insufficient data. Due to the design of the studies, the described outcomes were not blinded during the experiment. In the grouping process, only 2 articles[ 18 , 22 ] explicitly used allocation concealment. The quality of the other 3 articles[ 26-28 ] could not be fully evaluated because they had only abstracts. In addition, patients’ age, tests for diagnosing H. pylori infection, tests for confirming eradication , and HDDT and BQT regimens were not identical. All of these may lead to heterogeneity of the original results, which may influence the results of this meta-analysis. Lastly, studies included in this research mainly focused on the Asian region represented by China, and whether it is applicable to other regions of the world still needs further research.
In conclusion, this meta-analysis demonstrated that HDDT achieved a non-inferiority eradication rate, fewer side effects, and similar compliance compared with BQT. Of course, as research in this area is continuing and new evidence is emerging, the conclusions of this paper needs to be revised in light of future evidence.
Financial support and sponsorship
Innovative Research Program of Xiangyang No. 1 People’s Hospital (No. XYY2021Q15).
Conflicts of interest
There are no conflicts of interest.
Supplementary Figure 1
Risk of bias summary
Supplementary Figure 2
Egger’s plots of risk ratios for all studies in the meta-analyses. (a) the eradication rate of ITT analysis; (b) the eradication rate of PP analysis; (c) the adverse events analysis; (d) the compliance analysis
The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (https://links.lww.com/SJGA/A97
The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (https://links.lww.com/SJGA/A98
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