Meta-analysis of first-line triple therapy for helicobacter pylori eradication in Korea: is it time to change?

Proton pump inhibitor (PPI)-based triple therapy consisting of PPI, amoxicillin, and clarithromycin, is the recommended first-line treatment for Helicobacter pylori infection. However, the eradication rate of triple therapy has declined over the past few decades. We analyzed the eradication rate and adverse events of triple therapy to evaluate current practices in Korea. A comprehensive literature search was performed up to August 2013 of 104 relevant studies comprising 42,124 patients. The overall eradication rate was 74.6% (95% confidence interval [CI], 72.1%-77.2%) by intention-to-treat analysis and 82.0% (95% CI, 80.8%-83.2%) by per-protocol analysis. The eradication rate decreased significantly from 1998 to 2013 (P < 0.001 for both intention-to-treat and per-protocol analyses). Adverse events were reported in 41 studies with 8,018 subjects with an overall incidence rate of 20.4% (95% CI, 19.6%-21.3%). The available data suggest that the effectiveness of standard triple therapy for H. pylori eradication has decreased to an unacceptable level. A novel therapeutic strategy is warranted to improve the effectiveness of first-line treatment for H. pylori infection in Korea.

INTRODUCTION

Helicobacter pylori infection causes chronic gastritis and is associated with an increased risk of upper gastrointestinal diseases, such as peptic ulcer disease, gastric cancer, and mucosa-associated lymphoid tissue lymphoma (1, 2). Although its incidence has declined in developed countries, the prevalence of H. pylori remains high in Korea (3, 4, 5, 6). The nationwide seroprevalence surveys performed in 1998 and 2005 among asymptomatic Korean adults reported H. pylori prevalence rates of 66.9% and 59.5% (5).

Proton pump inhibitor (PPI)-based triple therapy, which consists of PPI, amoxicillin, and clarithromycin or metronidazole, is the first-line treatment for H. pylori infection (7). Because metronidazole-resistant H. pylori strains are reported in 40% or more of clinical isolates, triple therapy with PPI standard dose bis in die (bid, twice a day), amoxicillin 1 g bid, and clarithromycin 500 mg bid is the standard regimen for H. pylori eradication in Korea (7, 8, 9). However, even with the current treatment regimens, treatment fails in approximately 20% of patients who remain H. pylori positive (10, 11). In addition, the prevalence of clarithromycin-resistant H. pylori strains is increasing in both Korea and other countries, and the efficacy of PPI-based triple therapies has substantially decreased to 80% or below in most countries in recent decades (11, 12, 13, 14, 15, 16). Consequently, whether standard triple therapy should continue as first-line therapy is currently under debate.

Several observational studies assessing trends in H. pylori eradication over a number of years have been performed in Korea. In some reports, the eradication rate of standard triple therapy was shown to have decreased to 77.5% in recent years (15, 17). In contrast, other studies reported that the eradication rate remained constant over 5-11 yr, although the eradication rate was found to be below 90% in a per-protocol (PP) analysis (18, 19, 20). This discrepancy may be due to geographical differences in antibiotic resistance and to different methods used for determining eradication. We therefore performed a meta-analysis to evaluate the eradication rate and adverse events of first-line triple therapy to verify the effectiveness of current practice in Korea.

MATERIALS AND METHODS

Study selection

A comprehensive literature search was performed to identify relevant studies through August 2013 using computer-assisted bibliographic searches of PubMed, KoreaMed, and KMBASE. Combinations of the following terms were used: H. pylori or H. pylori and eradication, triple, first-line, proton pump inhibitor, PPI, amoxicillin, clarithromycin, or metronidazole. Abstracts and full papers from relevant studies were reviewed, and those meeting the defined selection criteria were considered for further evaluation. Abstracts presented through August 2013 at the following congresses were also hand-searched: Digestive Disease Week, the United European Gastroenterology Week, the Korean Society of Gastroenterology, the Korean College of Helicobacter and Upper Gastrointestinal Research, and the Korean Association of Internal Medicine. Abstracts of articles in each of these multiple searches were reviewed, and those meeting the inclusion criteria were included. Care was taken to avoid obtaining duplicate data by examining the authors' names and affiliations for each publication. Overlapping articles and articles unrelated to our analysis were excluded.

Studies were eligible if they had at least one treatment arm and met all of the following criteria: 1) assessed standard triple therapy (a PPI with amoxicillin and clarithromycin) for H. pylori eradication; 2) included first-line eradication therapy; 3) demonstrated H. pylori infection by at least one high-accuracy diagnostic test (urea breath test, stool antigen test, histological examination, rapid urease test, or culture); 4) confirmed eradication of infection after completion of treatment, based on an appropriate follow-up test; and 5) was the most informative article when multiple articles were published by the same authors or groups.

The quality of each randomized controlled study was assessed by using the Jaded composite scale based on three items: 1) randomization; 2) double blinding; and 3) description of withdrawals and dropouts (21). The selection of studies for this meta-analysis was performed by two independent reviewers. Differences between the two reviewers were resolved by assessment of the full article by a third reviewer. The decision as to whether to include the article was made by consensus.

Data extraction and analysis

Data on the following items were extracted from the selected articles: 1) study design; 2) study period; 3) number of patients enrolled in the study and in each treatment arm; 4) drug regimen, doses, and duration of therapy; 5) diagnostic tests used in the diagnosis of H. pylori infection and confirmation of eradication; 6) indications for H. pylori eradication; 7) number of patients in whom H. pylori infection was successfully eradicated; and 8) number of patients with adverse events and the type of adverse event.

To account for heterogeneity between studies, the overall and yearly eradication rates and their 95% confidence intervals (CIs) were estimated with a random-effect logistic regression model (PROC NLMIXED in SAS software version 9.2, Cary, NC, USA). All reported P values are two-sided, and values of P<0.05 indicated statistical significance.

RESULTS

We initially screened 282 studies. Of these, 112 reports of first-line standard triple therapy were included in the analysis (Fig. 1). After systematic review of these studies, a total of 104 studies including 38 randomized controlled trials (RCTs) and 66 observational studies were eligible for meta-analysis. The clinical characteristics of the studies are listed in Tables 1 and 2. A total of 42,124 subjects were included, and the sample size per study ranged from 12 to 4,198 subjects.

Fig. 1

Flowchart of the study design. RCT, randomized controlled trials.

Table 1

Characteristics of the randomized clinical studies included in the meta-analysis

AG, atrophic gastritis; C, culture; EGC, early gastric cancer; FHx, family history of gastric cancer; H, histology; MALT, mucosa-associated lymphoid tumor; NR, not reported; NUD, non-ulcer dyspepsia; PPI, proton pump inhibitor; PUD, peptic ulcer disease; R, rapid urease test; S, serology; U, urea breath test.

Table 2

Characteristics of the observational studies included in the meta-analysis

AG, atrophic gastritis; C, culture; EGC, early gastric cancer; FHx, family history of gastric cancer; H, histology; MALT, mucosa-associated lymphoid tumor; NR, not reported; NUD, non-ulcer dyspepsia; PPI, proton pump inhibitor; PUD, peptic ulcer disease; R, rapid urease test; S, serology; U, urea breath test.

The overall eradication rate with standard triple therapy was 74.6% (95% CI, 72.1%-77.2%) for intention-to-treat (ITT) analysis and 82.0% (95% CI, 80.8%-83.2%) for PP analysis. The eradication rate showed a decreasing tendency from the years 1998 to 2013 based on ITT and PP analysis (P<0.001 and P=0.0003, respectively) (Fig. 2). The eradication rates of the 7-day and 14-day treatments were 81.1% (95% CI, 79.8%-82.3%) and 85.3% (95% CI, 83.5%-87.1%) for PP analysis, respectively.

Fig. 2

Change in the eradication rate of the standard triple therapy by year. A decreasing trend was seen in the eradication rate during the last 16 yr (P < 0.001 for ITT analysis and P = 0.0003 for PP analysis). ITT, intention-to-treat; PP, per-protocol.

Adverse events were reported in 41 studies (24 RCTs and 17 observational studies) with 8,018 subjects treated with standard triple therapy (22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62). The incidence of adverse events in these studies was 20.4% (95% CI, 19.6%-21.3%). Taste alteration was the most common adverse event, followed by loose stool or diarrhea, abdominal discomfort, and nausea. The percentage of patients who stopped medication due to adverse events was 1.81% (35/1,930), suggesting that most patients could tolerate adverse events.

DISCUSSION

In our current study, we performed an up-to-date meta-analysis on the eradication rate of first-line PPI-based triple therapy. The results of our meta-analysis suggest that the efficacy of triple therapy for H. pylori infection is lower than desired, with a pooled eradication rate of 74.6% in ITT analysis and 82.0% in PP analysis. In addition, the eradication rate has significantly decreased over the last 16 yr.

Since 1998, PPI-based triple therapy has been recommended as the first-line therapy for H. pylori eradication in Korea. However, eradication rates have been declining, and, as of 2000, decreased to below 80% (11, 48), thereby failing to meet the requirements of the Asia-Pacific Consensus Guidelines, which state that a success rate of >80% in ITT analysis and >90% in PP analysis is needed for a regimen to be considered suitable for first-line eradication therapy (19, 42, 63).

There are several known factors that affect the eradication of H. pylori, such as antibiotic resistance, geographical area, patient age, smoking status, compliance, duration of therapy, bacterial density, Cag A, gastric acid concentration, individual response to PPI, and the presence of CYP2C19 polymorphism (10, 37, 64, 65). Among these factors, the main cause of the low eradication rate is presumed to be clarithromycin resistance. In Korea, the rate of resistance to clarithromycin was 5.9% before 2000, but has rapidly increased to 38.5% in the period of 2007 to 2009 (9, 16, 66, 67, 68). These rates are much higher than in other countries, such as Italy, and the main reason for this discrepancy may be the wide national and regional variations in the prevalence of antibiotic resistance (69). Clarithromycin resistance has been associated with cross-resistance caused by previous treatment with macrolides (70). In clinical practice, such antibiotics are usually prescribed for respiratory infections and are widely used for H. pylori eradication treatment. In addition, antibiotic treatment interruption due to gastrointestinal adverse events, such as diarrhea, nausea, vomiting, and abdominal discomfort, may be another reason for increased antibiotic resistance. Whereas an eradication rate higher than 75% is still achieved despite metronidazole resistance, clarithromycin resistance lowers the eradication rate by 20%, making it difficult to achieve an 80% eradication rate (71, 72). Potential approaches to overcome this resistance problem include patient-tailored, sequential, or concomitant therapies.

Increasing the duration of treatment may prove effective in curing infection, but this hypothesis remains to be validated. The majority of recently recommended eradication therapy regimens are 7-days in duration, which conveys advantages with respect to compliance and medical cost, while maintaining a similar eradication rate to that of longer regimens (73). The Asia-Pacific Consensus Guidelines and Japanese Consensus reports recommend a 7-day PPI-based triple therapy, whilst the Korean College of Helicobacter and Upper Gastrointestinal Research recommend 7-day or 14-day PPI-based triple therapy (74, 75). In Korea, 7-day PPI-based triple therapy has a PP eradication rate of 90%, which is not inferior to that of the 10-day or 14-day therapy (55, 60). However, in a recent study, although the 7-day PPI-based triple therapy was not inferior to the 14-day therapy, neither of the treatment durations provided an acceptable eradication rate of 90% in the PP analysis (11, 38). These studies, which were performed in Korea, were unable to provide conclusive evidence that a prolonged treatment for 2 weeks could counteract resistance to clarithromycin. Moreover, if the cause of treatment failure is antibiotic resistance, extension of the treatment period would not be expected to increase the eradication rate. Therefore, other strategies that achieve higher H. pylori eradication rates are needed, in addition to prolonged treatment duration, to increase the eradication rate in Korea.

Our present study is the largest study to date examining H. pylori eradication in Korea; however, there are several limitations. First, although we tried to include data from all over Korea, our data may not be representative of the entire Korean population. Second, we could not assess the antibiotic resistance rates and precise compliance rates in each study population. Therefore, there may be other factors not included in our analysis that influence the eradication rate of H. pylori.

In conclusion, conflicting results have been reported worldwide with regard to H. pylori eradication with standard triple therapy. Our data support the evidence for a decreased eradication rate of H. pylori, suggesting that a novel therapeutic strategy is warranted to improve first-line treatment for H. pylori infection in Korea.