A 10- or 14-day Bismuth-containing Quadruple Therapy as a First-line Helicobacter pylori Eradication Therapy: A Systematic Review and Meta-analysis

Article information

Korean J Helicobacter Up Gastrointest Res. 2021;21(1):48-58

Publication date (electronic) : 2021 January 28

doi : https://doi.org/10.7704/kjhugr.2020.0052

Sung Eun Kim^,1, Hye-Kyung Jung², Seung Joo Kang³, Yong Chan Lee⁴, Hyo-Joon Yang⁵, Seon-Young Park⁶, Cheol Min Shin⁷, Hyun Chul Lim⁸, Jie-Hyun Kim⁹, Su Youn Nam^10,11, Woon Geon Shin¹², Jae Myung Park¹³, Il Ju Choi¹⁴, Jae Gyu Kim¹⁵, Miyoung Choi¹⁶, Korean College of Helicobacter and Upper Gastrointesinal Research

¹Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea

²Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea

³Department of Internal Medicine, Seoul National University Hospital Gangnam Center, Seoul, Korea

⁴Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea

⁵Division of Gastroenterology, Department of Internal Medicine and Gastrointestinal Cancer Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

⁶Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea

⁷Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea

⁸Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea

⁹Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea

¹⁰Department of Gastroenterology, Center for Gastric Cancer, Kyungpook National University Hospital Chilgok Hospital, Daegu, Korea

¹¹Department of Gastroenterology, School of Medicine, Kyungpook National University, Daegu, Korea

¹²Department of Internal Medicine, Hallym University College of Medicine, Seoul, Korea

¹³Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea

¹⁴Center for Gastric Cancer, National Cancer Center, Goyang, Korea

¹⁵Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea

¹⁶Division of Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea

Corresponding author: Sung Eun Kim Department of Internal Medicine, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan 49267, Korea Tel: +82-51-990-5225, Fax: +82-51-990-5055, E-mail: solefide@hanmail.net

Received 2020 October 13; Revised 2020 November 6; Accepted 2020 November 10.

Abstract

INTRODUCTION

As of 2015, the global prevalence of Helicobacter pylori (H. pylori) was approximately 4.4 billion [1]. This common infection is well known to cause gastritis, peptic ulcers, gastric mucosa-associated lymphoid tissue lymphoma, and gastric cancer [2]. Therefore, effective eradication therapy is crucial for building public health, particularly in high H. pylori prevalence areas, including Korea.

According to Korean guidelines for the diagnosis and treatment of H. pylori infection, which were revised in 2013, standard triple therapy, comprising proton pump inhibitors (PPIs), amoxicillin, and clarithromycin, is the recommended first-line eradication regimen for H. pylori infection [3]. Unfortunately, the efficacy of the standard triple therapy is declining worldwide, and this tendency is also observed in Korea [4-6]. The H. pylori eradication rates in Korea using standard triple therapy were 84.9~87.5% from 2001 to 2007 and 80.0~81.4% from 2008 to 2010 (P<0.0001), presenting a decreasing trend for the last 10 years [5].

Several recognized guidelines recommended that standard triple therapy, sequential therapy (SQT), concomitant therapy (CT), bismuth-containing quadruple, or non-bismuth-containing quadruple therapies are a recommended first-line treatment option [7,8]. In the aforementioned revised Korean guidelines, when clarithromycin resistance is suspected, bismuth-containing quadruple therapy is used as the first-line therapy; however, it is generally recommended as a second-line regimen to eradicate H. pylori [3].

Bismuth-containing quadruple therapy is an effective regimen for H. pylori eradication. However, the efficacy of bismuth-containing quadruple therapy as a first-line treatment has depended on the type of eradication regimens and duration of therapies in two network meta-analyses of the randomized controlled trials (RCTs) [9,10]. With this background, a meta-analysis was conducted to evaluate the efficacy and safety of bismuth-containing quadruple therapy for first-line H. pylori eradication and compare it to standard triple therapy, SQT, and CT, which are commonly used as first-line eradication therapies.

MATERIALS AND METHODS

RESULTS

1. Study selection

A total of 204 studies were reviewed. Fig. 1 shows the flow diagram of the literature search. Subsequently, we excluded 172 studies after reviewing the title or abstract, and we reviewed full articles or abstracts for 32 studies. Among them, 25 studies were excluded according to the selection criteria. Finally, seven RCTs with 3,653 patients were enrolled for meta-analysis [13-19]. The study design of five trials was multiple arms; therefore, the data of the groups that accorded with the inclusion criteria were selected and included for analysis.

Fig. 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram of the study selection. PPIs, proton pump inhibitors.

2. Characteristics of studies and risk of bias

Table 1 presents the main characteristics of the studies. All studies used a first-line bismuth-containing quadruple therapy consisting of PPIs (pantoprazole, rabeprazole, or lansoprazole), bismuth compounds (bismuth subcitrate, bismuth tripotassium dicitrate, bismuth potassium citrate, colloidal bismuth subcitrate, or bismuth subsalicylate), metronidazole, and tetracycline (PBMT). Patients who received PBMT were 1,206, and 2,447 patients were treated with non-PBMT regimens. Among the non-PBMT regimen groups, 753 patients of three trials in standard triple therapy group, 230 patients in two trials in the SQT group, and 770 patients of three trials in the CT group were eligible to subgroup analysis for eradication efficacy. The risks of bias assessment in seven trials are shown in Supplementary Table 1.

Table 1.

Characteristics of the Studies Included in the Meta-analysis

4. Eradication rates between PBMT and standard triple therapy

Of three trials, 759 patients were prescribed PBMT for 10 or 14 days, and 753 patients received standard triple therapy for 14 days (Fig. 2). When we compared eradication rates between 10- or 14-day PBMT and 14-day standard triple therapy, the differences were not statistically significant in ITT and PP analyses (ITT analysis: RR, 1.28; 95% CI, 0.97~1.70; P=0.08; PP analysis: RR, 1.37; 95% CI, 0.95~1.99; P=0.10). However, heterogeneity among the studies was high in the ITT and PP analyses (ITT analysis: χ²=10.14, P=0.006, I²=80%; PP analysis: χ²=20.95, P<0.001, I²=90%).

Fig. 2.

Forest plot of Helicobacter pylori eradication of 10- or 14-day bismuth-containing quadruple therapy (PMBT) vs. 14-day standard triple therapy (STT) as the first-line therapy. (A) Intention-to-treat analysis. (B) Per-protocol analysis. Risk of bias: A, random sequence generation (selection bias); B, allocation concealment (selection bias); C, blinding of participants and personnel (performance bias); D, blinding of outcome assessment (detection bias); E, incomplete outcome data (attrition bias); F, selective reporting (reporting bias); G, other bias. M-H, Mantel-Haenszel test.

5. Eradication rates between PBMT and SQT

Each of 230 patients were treated with 10- or 14-day PBMT and 10-day SQT (Fig. 3). Eradication rates between 10- or 14-day PBMT and 10-day SQT were not significantly different in ITT and PP analyses (ITT analysis: RR, 0.96; 95% CI, 0.83~1.12; P=0.59; PP analysis: RR, 0.99; 95% CI, 0.93~1.05; P=0.67). Heterogeneity between the studies was moderate in ITT analysis (χ²=2.08, P=0.15, I²=52%), and low in PP analysis (χ²=0.22, P=0.64, I²=0%).

Fig. 3.

Forest plot of Helicobacter pylori eradication of 10- or 14-day bismuth-containing quadruple therapy (PBMT) vs. 10-day sequential therapy (SQT) as the first-line therapy. (A) Intention-to-treat analysis. (B) Per-protocol analysis. Risk of bias: A, random sequence generation (selection bias); B, allocation concealment (selection bias); C, blinding of participants and personnel (performance bias); D, blinding of outcome assessment (detection bias); E, incomplete outcome data (attrition bias); F, selective reporting (reporting bias); G, other bias. M-H, Mantel-Haenszel test.

6. Eradication rates between PBMT and CT

Each of 770 patients received PBMT for 10 or 14 days and CT for 10 days (Fig. 4). There were no significant differences between 10- or 14-day PBMT and 10-day CT groups in either analyses (ITT analysis: RR, 1.01; 95% CI, 0.93~1.10; P=0.83; PP analysis: RR, 1.01; 95% CI, 0.95~1.07; P=0.83). Moderate heterogeneity in the studies was revealed in both the ITT and PP analyses (ITT analysis: χ²=4.57, P=0.10, I²=56%; PP analysis: χ²=5.51, P=0.06, I²=64%).

Fig. 4.

Forest plot of Helicobacter pylori eradication with 10- or 14-day bismuth-containing quadruple therapy (PBMT) vs. 10-day concomitant therapy (CT) as the first-line therapy. (A) Intention-to-treat analysis. (B) Per-protocol analysis. Risk of bias: A, random sequence generation (selection bias); B, allocation concealment (selection bias); C, blinding of participants and personnel (performance bias); D, blinding of outcome assessment (detection bias); E, incomplete outcome data (attrition bias); F, selective reporting (reporting bias); G, other bias. M-H, Mantel-Haenszel test.

7. Adverse events

All seven trials identified adverse events with treatment. With regard to the duration of the treatment, the pooled adverse event rate of 10-day PBMT were 44.6% (95% CI, 22.5~69.1%) and those of 14-day PBMT were 55.9% (95% CI, 27.6~80.8%). The meta-analysis of these trials revealed that the frequency of adverse events was significantly higher in patients with PBMT than in those with non-PBMT, and the pooled RR for adverse events was 1.64 (95% CI, 1.11~2.44; P=0.01) (Fig. 5). However, significant heterogeneity in adverse event was observed in the trials (χ²=88.7, P<0.001, I²=93%).

Fig. 5.

Forest plot of Helicobacter pylori eradication with bismuth-containing quadruple therapy (PBMT) vs. non-bismuth-containing quadruple therapy as the first-line therapy. Risk of bias: A, random sequence generation (selection bias); B, allocation concealment (selection bias); C, blinding of participants and personnel (performance bias); D, blinding of outcome assessment (detection bias); E, incomplete outcome data (attrition bias); F, selective reporting (reporting bias); G, other bias. M-H, Mantel-Haenszel test.

DISCUSSION

Eradication rate of H. pylori is closely related to antibiotics resistance. Among them, the resistance of clarithromycin reduces the success rate of H. pylori eradication. A recent meta-analysis reported that the pooled RR of the eradication rate was 0.682 (95% CI, 0.636~0.731) in patients with H. pylori strains sensitive versus resistant to clarithromycin, whereas the pooled RR of the eradication rate was 0.843 (95% CI, 0.810~0.877) and 0.794 (95% CI, 0.669~0.941) in patients with H. pylori strains sensitive versus resistant to metronidazole and levofloxacin, respectively [20]. Compared to other antibiotics, clarithromycin had the most pervasive influence in eradication rates.

High clarithromycin resistance areas are commonly defined as the clarithromycin resistance rate of H. pylori, which is at least 15% [7]. Clarithromycin resistance has increased during the last decade in Korea [21], and recent Korean studies still presented that clarithromycin resistance rates were 17.8~31.0% [22,23]. At least for first-line H. pylori eradication therapy, successful eradication rates should be more than 80% in ITT analysis and more than 90% in PP analysis [24]. Established guidelines recommended that bismuth-containing quadruple or non-bismuth-containing quadruple therapies are appropriate as the first-line H. pylori eradication therapy in areas of high clarithromycin resistance [7,8]. This meta-analysis revealed that the pooled eradication rate for PBMT as a first-line eradication therapy was 82.1% and 88.8% in ITT and PP analyses. Although the eradication rate in PP analysis did not reach 90%, the effect of PBMT was assumed to be sufficient because the eradication rate was almost 90%.

Nonetheless, when we compared the eradication rates between PBMT and other widely used first-line eradication regimens, there were no statistically significant differences of eradication rates in 10- or 14-day PBMT with 10-day SQT (RR, 0.99; 95% CI, 0.93~1.05), 10-day CT (RR, 1.01; 95% CI, 0.95~1.07), or even 14-day standard triple therapy (RR, 1.37; 95% CI, 0.95~1.99). Our results indicate that 14-day standard triple therapy, 10-day SQT, and 10-day CT are not inferior to 10- or 14-day PBMT.

Duration of treatment can affect the H. pylori eradication rate, and regimens of longer duration had higher eradication rates than did regimens of shorter duration [10]. In terms of standard triple therapy, 14-day standard triple therapy (OR, 1.72; 95% CI, 1.37~2.17) and 10-day standard triple therapy (OR, 1.32; 95% CI, 1.04~1.69) showed a higher eradication rate than did 7-day standard triple therapy [10]. Several meta-analyses have demonstrated similar results for standard triple therapy [7,9,25]. Although the eradication rates of standard triple therapy tend to decrease, 14-day standard triple therapy could be an acceptable regimen, since it has a higher therapeutic effect than does standard triple therapy with a shorter duration.

The results obtained in our study comparing PBMT and SQT are consistent with previous meta-analyses. According to the systematic review and meta-analysis study which analyzed 46 RCTs with 13,532 patients, the overall eradication rate of SQT was 84.3% (95% CI, 82.1~86.4%) [26]. SQT was superior to 7-day standard triple therapy (RR, 1.21; 95% CI, 1.17~1.25) and 10-day standard triple therapy (RR, 1.11; 95% CI, 1.04~1.19) [26]. However, SQT was not superior to 14-day standard triple therapy (RR, 1.00; 95% CI, 0.94~1.06) and 10- or 14-day of bismuth-containing quadruple therapy (RR, 1.01; 95% CI, 0.95~1.06) [26].

Two prospective studies comparing PBMT and CT as first-line treatment were recently published, and CT showed high eradication rates in both studies. A study from Spain reported that the eradication rate was 98.0% (95% CI, 94~100%) in a 14-day CT group and 94.4% (95% CI, 88.1~100%) in a 10-day PBMT group at ITT analysis (P=0.346) [27]. There was no significant difference in adverse events rates between CT (56.0%) and PBMT (46.3%) (P=0.323) [27]. The other was a Korean study that conducted a prospective open-label randomized trial comparing 14-day modified PBMT and 14-day CT [28]. The ITT eradication rate was 88.2% in a modified PBMT group and 79.4% in a CT group (P=0.162) [28]. PP eradication rates were 98.4% and 93.1% in the modified PBMT and CT groups, respectively (P=0.199) [28]. Adverse events rates were higher in CT (51.5%) than in modified PBMT (33.8%) patients (P=0.037) [28]. The adverse event rates of both studies were higher in the CT group than in the PBMT group; however, it should be considered that the duration of CT is longer than that of PBMT in the Spanish study, and the Korean study used modified PBMT that was prescribed PBMT twice a day. A meta-analysis of 19 clinical trials with 2,070 patients reported that a mean ITT cure rate was 88% (95% CI, 85~91%) for CT [29].

It is already known that adverse events of PBMT are common. The adverse events rates of PBMT typically arise in 50% or more [30]. The rates of adverse events were 67% (358/533) in 10-day PBMT, 58% (309/535) in 10-day CT, and 47% (252/535) in 14-day standard triple therapy groups in a multi-center, randomized trial from Taiwan [15]. Although we observed considerable heterogeneity among trials, the adverse events of PBMT were significantly higher than in other eradication therapies (RR, 1.64; 95% CI, 1.11~2.44) in the current meta-analysis. A recent network meta-analysis including 35 studies with 10,860 patients for demonstrating adverse events reported that PBMT showed more adverse events than did SQT and CT [31]. Compared to 14-day PBMT, 14-day SQT (OR, 0.42; 95% CI, 0.22~0.80), 10-day SQT (OR, 0.49; 95% CI, 0.31~0.78), and 10- or 14-day CT (OR, 0.57; 95% CI, 0.37~0.89) therapies were significantly lower in the adverse events rates [31]. There was no significant difference in rates of adverse events between PBMT and standard triple therapy groups in other meta-analyses; however, the overall incidence of adverse events was 46% in PBMT and 46.3% in the standard triple therapy groups [32]. Therefore, the adverse events of PBMT are an issue to consider in clinical practice when using PBMT regimens.

Another problem to take account of in prescribing PBMT is rescue therapy related. It is difficult to decide on a rescue therapy after failure of PBMT. The Maastricht V/Florence consensus report recommended a quinolone-containing triple or quadruple therapy in patients who failed with PBMT [7]. In high quinolone-resistance areas, it is recommended to use the combination of bismuth with other antibiotics [7]. The revised Korean guideline recommended a rescue regimen containing two or more antibiotics that had not been included in PBMT in patients with eradication failure for PBMT [3]. Given the quinolone resistance to H. pylori, the resistance rates of both levofloxacin and moxifloxacin revealed a tendency to increase time-dependently (4.7~28.1%, P=0.002) in Korea [21]. A recent Korean study showed that the resistance rates of both levofloxacin and ciprofloxacin were 37.0% [33]. Another study from Korea compared 7-day PBMT with 14-day moxifloxacin triple therapy as a second-line H. pylori eradication therapy [34]. Eradication rates were 93.6% (95% CI, 91.0~95.9%) and 73.8% (95% CI, 63.1~84.6%) in 7-day PBMT and 14-day moxifloxacin triple therapy groups, respectively (P<0.001) [34]. Despite the shorter duration of PBMT, it exhibited a higher eradication rate than did the longer duration of moxifloxacin triple therapy. H. pylori culture and antimicrobial susceptibility testing are preferred methods to be used after eradication failure of PBMT regimens [7]. Actually, few laboratories have been installed with these systems in Korea. Thus, though PBMT is a valuable treatment for H. pylori infection, PBMT as a first-line therapy could be recommended for patients with an allergy to penicillin, with a clarithromycin-resistant H. pylori infection, or with a history of previous macrolide use.

This study has several limitations. First, only a few trials were included in our analysis, and heterogeneities among studies were generally moderate or high. Therefore, this should be considered when interpreting our results. Second, studies from Korea could not be analyzed because there are no randomized controlled Korean studies on this subject. However, several Turkish and Taiwanese studies were included in this analysis. Turkey belonged to areas of high H. pylori prevalence (77.2%) [1] and high clarithromycin resistance (28%) [35]. The prevalence of H. pylori infection in Taiwan was 53.9% [1] and clarithromycin resistance was 26% [35]. Therefore, these results could reflect those in Korea.

In conclusion, PBMT can be a first-line treatment for H. pylori eradication when other first-line options are unavailable, because of its high adverse events rate and its potential for use as rescue therapy. Further well-designed studies are needed to prove the efficacy of PBMT for first-line H. pylori eradication in Korea.

Supplementary Materials

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