DOI: 10.1111/hel.

12389

REVIEW ARTICLE

Efficacy of Helicobacter pylori eradication therapies in Korea: A

systematic review and network meta-­analysis

Yoon Suk Jung1 | Chan Hyuk Park2  | Jung Ho Park1 | Eunwoo Nam3 | Hang Lak Lee4

1
Division of Gastroenterology, Department
of Internal Medicine, Kangbuk Samsung Abstract
Hospital, Sungkyunkwan University School of Background: The efficacy of Helicobacter pylori eradication regimens may depend on
Medicine, Seoul, Korea
2
the country where the studies were performed because of the difference in antibiotic
Department of Internal Medicine, Hanyang
University Guri Hospital, Hanyang University resistance. We aimed to analyze the efficacy of H. pylori eradication regimens in Korea
College of Medicine, Guri, Korea
where clarithromycin resistance rate is high.
3
Biostatistical Consulting and Research
Methods: We searched for all relevant randomized controlled trials published until
Lab, Medical Research Coordinating
Center, Hanyang University, Seoul, Korea November 2016 that investigated the efficacy of H. pylori eradication therapies in
4
Division of Gastroenterology, Department Korea. A network meta-­analysis was performed to calculate the direct and indirect
of Internal Medicine, Hanyang University
Hospital, Hanyang University College of estimates of efficacy among the eradication regimens.
Medicine, Seoul, Korea Results: Forty-­three studies were identified through a systematic review, of which 34

Correspondence
Chan Hyuk Park, Department of Internal
Medicine, Hanyang University Guri Hospital,
Hanyang University College of Medicine, Guri,
Korea.
Email: yesable7@gmail.com
studies, published since 2005, were included in the meta-­analysis. Among 21 included
regimens, quinolone-­containing sequential therapy for 14 days (ST-­Q-­14) showed the
highest eradication rate (91.4% [95% confidence interval [CI], 86.9%-­94.4%] in the
intention-­to-­treat [ITT] analysis). The eradication rate of the conventional triple ther-
apy for 7 days, standard sequential therapy for 10 days, hybrid therapy for 10-­14 days,
and concomitant therapy for 10-­14 days was 71.1% (95% CI, 68.3%-­73.7%), 76.2%
(95% CI, 72.8%-­79.3%), 79.4% (95% CI, 75.5%-­82.8%), and 78.3% (95% CI, 75.3%-­
80.9%), respectively, in the ITT analysis. In the network meta-­
analysis, ST-­
Q-­
14
showed a better comparative efficacy than the conventional triple therapy, standard
sequential therapy, hybrid therapy, and concomitant therapy. In addition, tolerability
of ST-­Q-­14 was comparable to those regimens.
Conclusion: In Korea, ST-­Q-­14 showed the highest efficacy in terms of eradication
and a comparable tolerability, compared to the results reported for the conventional
triple therapy, standard sequential therapy, hybrid therapy, and concomitant therapy.

KEYWORDS
antibiotics, eradication therapy, Helicobacter pylori, network meta-analysis, tolerability

1 |  INTRODUCTION prevented after H. pylori eradication.5 In addition, H. pylori eradication

Approximately half of the world’s population is reported to have
1
Helicobacter pylori infection, which can cause various diseases, includ-
ing peptic ulcer, gastric mucosa-­associated lymphoid tissue (MALT)
lymphoma, immune thrombocytopenic purpura, and gastric cancer.2-4
MALT lymphoma and immune thrombocytopenic purpura can be con-
5
trolled through H. pylori eradication. Recurrence of peptic ulcer can be
may reduce the incidence of gastric cancer in healthy asymptomatic-­
infected individuals, particularly in Asia.6
Helicobacter pylori eradication rate has been improved after the
development of proton-­pump inhibitors (PPIs) approximately 25 years
ago.7 PPI-­based therapy showed a superior efficacy to that of non-­
PPI-­based therapy in terms of H. pylori eradication.8 Therefore, the
conventional triple therapy, which consists of PPI, amoxicillin, and

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clarithromycin, has been a worldwide choice for H. pylori eradica-
tion.5,9,10 However, the eradication rate of the conventional triple
therapy has decreased in recent years because of the increase in
antibiotic resistance.11-15 To improve the eradication rate, alternative
regimens have been suggested, including sequential, concomitant, and
16-18
hybrid therapies.
Many head-­to-­head trials were performed to compare H. pylori
eradication rates among various regimens, and the relative efficacy
of these regimens has been analyzed via pairwise meta-­analyses.19-22
However, establishment of the optimal regimen is still a challenge
because of two major reasons. First, the eradication rate of H. pylori
eradication regimens may depend on the country where the studies
were performed because of the difference in antibiotic resistance.23
The estimates based on worldwide trials may be limited to guide clini-
cians to select optimal regimens. Therefore, the results of the studies
conducted in the same region need to be summarized for understand-
ing the efficacy of various eradication regimens in a given country.
Second, traditional pairwise meta-­analysis is difficult to integrate and
cannot systematically compare more than two eradication regimens.
Indirect estimates from studies comparing treatments of interest with
a common comparator should be considered for analyzing the relative
24
efficacy of multiple treatment regimens.
Previous meta-­
analyses reported inconsistent results of com-
parative efficacy among the eradication regimens.19,20 For example,
a previous meta-­analysis for Asian studies showed that the sequen-
tial therapy was superior in terms of eradication to the conventional
triple therapy.20 However, the Cochrane review published in 2016
demonstrated that recent studies did not show different eradication
rate between the sequential and conventional triple therapies.19 Such
a discrepancy may be due to the geographic distribution of antibiotic
resistance, especially for clarithromycin.23
In Korea, clarithromycin resistance rate remained high in recent
15 years. It was 17.2%, 21.4%, and 23.4% in 2003-­2005, 2006-­2008,
and 2009-­2012, respectively.12 In this study, we comprehensively
analyzed the efficacy of H. pylori eradication regimens in Korea. The
analysis may also be helpful to understand the efficacy of eradication
regimens in other countries where clarithromycin resistance rate is
high. We searched for all the published randomized controlled trials
(RCTs) on H. pylori eradication in Korea, including studies published
in Korean as well as English. Then, a network meta-­analysis was per-
formed to calculate the indirect and mixed estimates (from direct and
indirect estimates) for evaluating efficacy of each H. pylori eradica-
tion regimen.
2 |  METHODS
This systematic review and network meta-­
analysis were con-
ducted according to the Preferred Reporting Items for Systematic
Reviews and Meta-­Analyses (PRISMA) statement25 and the report
of the International Society for Pharmacoeconomics and Outcomes
Research Task Force on Indirect Treatment Comparisons Good
Research Practices.24
2.1 | Search strategy
We searched for all relevant studies published between January 1990
and November 2016 that investigated the efficacy of H. pylori eradi-
cation therapies using MEDLINE, EMBASE, the Cochrane Library, and
KoreaMed databases. The following search string was used ((helico-
bacter) OR (campylobacter) OR (pylori*)) AND ((eradication) OR (treat-
ment)) AND (korea*). The detailed search strategies for each database
are shown in Appendix 1. To identify additional studies, we also exam-
ined the references of the screened articles. The latest date for updat-
ing our search was November 30, 2016.
2.2 | Study selection
In the first step for study selection, the titles and abstracts of arti-
cles retrieved by our keyword search were examined to exclude
the irrelevant articles. Next, the full text of all the selected studies
was screened according to our inclusion and exclusion criteria. The
inclusion criteria were as follows: (i) patients: treatment-­naïve adult
patients with H. pylori infection, (ii) intervention: H. pylori eradication,
(iii) comparator: another regimen for H. pylori eradication, and (iv) out-
come: H. pylori eradication rate and tolerability. The exclusion criteria
included (i) nonoriginal or unpublished studies and (ii) non-­RCTs.
All the included studies according to the inclusion/exclusion cri-
teria were reviewed. However, studies published before 2005 were
excluded in the quantitative synthesis (meta-­analysis) because antibi-
otic resistance rate has changed over time.11,12
Two investigators (Y. S. J. and C. H. P.) independently evaluated
the studies for eligibility and resolved any disagreements through
discussion and consensus. If agreement could not be reached, a third
investigator (J. H. P.) determined the study eligibility. The Cochrane
Risk of Bias assessment tool was used for assessing the risk of bias in
individual studies.26
2.3 | Data extraction
Using a data extraction form developed in advance, two reviewers
(Y. S. J and C. H. P) independently extracted the following informa-
tion: the first author, year of publication, study design, country, study
period, publication language, eradication regimens, confirmative test
for eradication, eradication rate (intention-­
to-­
treat [ITT] and per-­
protocol [PP] analyses), tolerability, and adverse events.
The primary end point of this meta-­analysis was the pooled erad-
ication rate in the ITT analysis. The secondary end point was the
comparative efficacy in terms of H. pylori eradication rate and the
tolerability.
2.4 | Statistical analysis
Meta-­analysis was conducted to calculate the pooled eradication rate
with 95% confidence interval (CI) for each eradication regimen using a
random effects model. A frequentist network meta-­analysis was per-
formed to calculate the direct and indirect estimates and to combine
JUNG et al.
the mixed estimates.27 If no event (or nonevent) was observed in
both arms of the comparison, we performed zero-­cell corrections
prior to meta-­analysis by adding 0.5 to all cells of the result table in
the individual studies in order to avoid computational errors because
of dividing by a zero count.28 In addition, design-­based decomposi-
tion of Cochran’s Q was performed for assessing the homogeneity
of whole network and that within the designs.29-31 Cochran’s Q test
was considered statistically significant if P<.1. In addition, H. pylori
eradication regimens was ranked according to the P-­scores, which
were based solely on the point estimates and standard errors of the
network estimates.32 They measured the extent of certainty that a
treatment is better than another one, averaged over all the competing
treatments.32 Pooled eradication rate of each regimen was calculated
using Comprehensive Meta Analysis (version 2.2.064; Biostat Inc.,
Englewood, NJ, USA). Network meta-­analysis was conducted using
the statistical software R (version 3.3.1; R Foundation for Statistical
Computing, Vienna, Austria) with netmeta package (version 0.9-­1;
Rücker et al.). The netmeta package is based on the graph theory
methodology to model the relative treatment effects of multiple treat-
ments under a frequentist framework.33
3 | RESULTS
3.1 | Study selection
A flow diagram for our systematic review is shown in Figure 1. A
total of 2236 studies were identified by our literature search. After
scanning the titles and abstracts, we discarded 731 duplicate articles,
which were retrieved through multiple search engines. Another 1447
irrelevant articles were excluded based on the titles and abstracts.
After the full texts of the 58 remaining articles were reviewed, 15
were excluded because of the following reasons: (i) two nonoriginal
studies, (ii) six retrospective studies, (iii) six studies with uncertain
study design, and (iv) one duplicate publication in a non-­English lan-
guage journal. As a result, the remaining 43 studies were included in
our systematic review and qualitative synthesis.34-76 Among them,
nine studies published before 2005 were excluded from the quantita-
tive synthesis.34-42 Finally, 34 studies were included in the network
meta-­analysis.43-76
3.2 | Study characteristics and risk of
bias assessment
The study characteristics and detailed information about H. pylori
eradication regimens are shown in Tables 1 and S1, respectively. All
studies were published between 1994 and 2017 with an enrollment
period that ranged from 1993 to 2015. The latest study published in
2017 was identified through our literature search; it was published
online ahead of print on August 9, 2016.76 Among the 34 studies
included in the meta-­analysis, four were published in Korean, and 30
studies were published in English. They included 11 332 participants.
Six studies included only patients with peptic ulcer, low-­grade gas-
tric MALT lymphoma, or endoscopically resected early gastric cancer,
|
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which were the indications covered by the Korean National Health
Insurance, whereas the other studies included patients regardless of
the indications (ie gastritis, erosion, or dyspepsia).
Overall, the conventional triple therapy for 7 days (TT-­
7) was
the most frequently compared regimen, which was included in 24
­studies. Sequential therapy for 10 days (ST-­10) was the second most
­commonly compared regimen, which was included in 14 studies. The
network of the 34 studies included in the network meta-­analysis is
shown in Figure 2. The comparative efficacy of TT-­7 vs that of ST-­10
was analyzed in seven of the 34 studies. Characteristically, TT-­7 was
compared with several regimens, including additive drugs, such as
probiotics (in three studies), mucoprotective agents (in two studies),
aspirin (in one study), and pronase (in one study). To minimize effect
of treatment duration on the eradication rate, several studies com-
pared the eradication rates among the conventional triple therapy,
sequential therapy, and concomitant therapy with the same treatment
duration (conventional triple therapy for 10 days [TT-­10] vs ST-­10 in
three studies, TT-­10 vs concomitant therapy for 10 days [CT-­10] in
two studies, and ST-­10 vs CT-­10 in two studies).
Quality assessments for individual studies are presented in Fig. S1.
Before 2005, eight of nine studies (88.9%) had unclear risk of bias in
the domain of random sequence generation. However, since 2005, 25
of 34 studies (73.5%) showed a low risk of bias, whereas seven (20.6%)
and two (5.9%) had unclear and high risk of bias, respectively, in terms
of random sequence generation. Overall, most studies showed unclear
(37 studies, 86%) or high (two studies, 4.7%) risk of bias in the domain
of allocation concealment. Performance and detection bias were
assessed as low risk in all studies because H. pylori eradication is not
affected by blinding of the participants or investigators. In addition,
there was no attrition bias in all studies. Seven studies (16.3%) was
classified as having high risk of reporting bias because they did not
assess some of the outcomes among the eradication rates in ITT and
PP analyses, and tolerability. However, since 2005, all studies assessed
the eradication rates in both the ITT and PP analyses.
3.3 | Pooled eradication rate of each regimen
Pooled eradication rates of H. pylori eradication regimens included in
the meta-­analysis are demonstrated in Table 2. Among 21 included
regimens, quinolone-­containing sequential therapy for 14 days (ST-­
Q-­14) showed the highest eradication rate (91.4% [95% CI, 86.9%-­
94.4%] in the ITT analysis). The eradication rate of the TT-­7, TT-­10,
and conventional triple therapy for 14 days (TT-­14) was 71.1% (95%
CI, 68.3%-­73.7%), 67.0% (95% CI, 60.0%-­73.4%), and 76.4% (95% CI,
73.3%-­79.2%), respectively, in the ITT analysis. In addition, ST-­10,
sequential therapy for 14-­15 days (ST≥14), hybrid therapy for 10-­
14 days (HT≥10), and concomitant therapy for 5-­7 days (CT≤7) and
10-­14 days (CT≥10) was 76.2% (95% CI, 72.8-­79.3%), 76.3% (95% CI,
72.2%-­80.0%), 79.4% (95% CI, 75.5%-­82.8%), 80.0% (95% CI, 75.1%-­
84.1%), and 78.3% (95% CI, 75.3%-­80.9%), respectively.
In the PP analysis, ST-­Q-­14, CT≤7, and CT≥10 had 93.9% (95%
CI, 89.8%-­96.4%), 92.9% (95% CI, 89.0%-­95.5%), and 91.0% (95% CI,
85.4%-­94.6%) of eradication rates, respectively.
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F I G U R E   1   Flow diagram of the studies included in the meta-­analysis
3.4 | Changes in the eradication rate by year
Changes in the eradication rate in ITT analysis of the major regimens
by publication year are shown in Fig. S2A. Studies published before
2005 were included in this longitudinal analysis. Eradication rates
of TT-­7 in ITT analysis ranged from 56.3% to 80.1%. Recently, the
eradication rates of TT-­7 were not high (72.6%, 64.3%, 69.3%, and
70.8% in 2013, 2014, 2015, and 2016, respectively). Most studies
on sequential or concomitant therapies were performed in the last
5 years. Although ST-­10, ST≥14, and CT≥10 generally seemed to
exhibit high eradication rates compared to the conventional triple
therapies between 2013 and 2016, these rates were insufficient to be
adopted as a primary therapy for H. pylori eradication (between 2013
and 2017: ST-­10, 72.1%-­77.6%; ST≥14, 71.6%-­80.0%; and CT≥10,
76.7%-­80.8%). The two studies on ST-­Q-­14 were performed in 2015,
and the eradication rate of ST-­Q-­14 was the highest among all regi-
mens (91.4% [95% CI, 86.9%-­94.4%]).
Figure S2B shows the changes in the eradication rate in PP analysis of
regimens by publication year. In 2015, ST-­Q-­14 had the highest eradication
rate among all regimens (93.9% [95% CI, 89.8%-­96.4%]). Between 2016
and 2017, CT≥10 showed high eradication rates in PP analysis (2016:
94.4% [95% CI, 89.2%-­97.2%]; 2017: 97.0% [95% CI, 92.4%-­98.9%]).
T A B L E   1   Characteristics of the studies included in the meta-­analysis

Definition of good Eradication rate, %

JUNG et al.

Year of Study Indication of tolerability, % dose Confirmative test Tolerability, Adverse

Author publication Language period Patients eradication Eradication regimen of administration for eradication ITT analysis PP analysis % event, %

Park34 1994 English 1993 144 Peptic ulcer or A: Bismuth-­based TT-­28 NA RUT and A: 82.3a, 72.9b NA A: 100.0 A: 25.0
gastritis B: TT-­bismuth-­28 Histopathologic B: 89.6a, 83.3b B: 100.0 B: 12.5
examination
Hahm35 1998 English NA 57 Peptic ulcer A: DT-­14 NA UBT, RUT, and A: 57.1 NA NA NA
B: DT-­14+mucoprotective histopathologic B: 75.0
agent examination
Ko36 1998 Korean 1996-­1997 334 Peptic ulcer A: Bismuth-­based TT-­14 NA RUT and A: 54.5 A: 92.3 A: 90.9 A: 27.3
B: Bismuth-­based TT-­7 histopathologic B: 33.3 B: 88.0 B: 95.5 B: 21.2
C: TT-­14 examination C: 57.4 C: 88.6 C: 98.1 C: 25.9
D: TT-­10 D: 47.8 D: 89.2 D: 100.0 D: 13.0
E: TT-­7 E: 58.2 E: 85.2 E: 100.0 E: 20.3
Na37 1998 Korean 1996 75 Peptic ulcer A: DT-­14 NA RUT and A: 52.0 A: 56.5 A: 100.0 NA
B: TT-­M-­14 histopathologic B: 88.0 B: 88.0 B: 100.0
C: TT-­M-­7 examination C: 72.0 C: 78.3 C: 100.0
Kim38 1999 Korean 1996-­1997 96 Peptic ulcer A: DT-­14 NA RUT A: 57.1 A: 57.1 A: 100.0 A: 7.1
B: Bismuth-­based TT-­14 B: 91.7 B: 91.7 B: 100.0 B: 25.0
C: TT-­10 C: 91.4 C: 91.4 C: 100.0 C: 5.7
Shim39 2000 Korean 1998 41 Duodenal ulcer A: TT-­7 ≥90 Histopathologic NA A: 57.1 A: 100.0 NA
B: TT-­M-­7 examination and B: 75.0 B: 100.0
culture
Cho40 2001 Korean NA 255 Peptic ulcer A: TT-­7 ≥80 UBT A: 74.4 NA NA A: 15.9
B: TT-­10 B: 80.2 B: 18.6
C: TT-­14 C: 92.0 C: 23.0
Lee41 2001 Korean 1999-­2000 50 Peptic ulcer A: H2RA-­based TT-­7 NA UBT and A: 80.0 A: 95.2 A: 100.0 A: 40.0d
B: TT-­7 histopathologic B: 76.0 B: 86.4 B: 100.0 B: 32.0d
examination
Choi42 2002 English 1997-­1998 321 Duodenal A: TT-­7 ≥75 UBT and RUT A: 70.9 A: 90.1 A: 100.0 NA
ulcer, gastritis B: TT-­M-­7 B: 64.8 B: 84.1 B: 97.6
Jang43 2005 Korean 2003-­2004 149 Peptic ulcer A: TT-­7 ≥80 UBT A: 78.7 A: 85.5 A: 98.6 A: 6.7
B: BQT-­7 B: 71.6 B: 85.5 B: 93.9 B: 9.5
Park44 2005 English 2003-­2004 122 Peptic ulcer, A: TT-­7 >85 RUT and A: 80.3 A: 80.3 A: 100.0 A: 41.0
gastritis B: TT-­7+aspirin histopathologic B: 85.2 B: 86.7 B: 100.0 B: 49.2
examination
Lee45 2006 Korean 2004-­2005 267 Any A: TT-­Q-­7 NA UBT A: 52.5 A: 69.8 A: 100.0 A: 1.4
B: TT-­7 B: 56.3 B: 74.0 B: 100.0 B: 4.0
Kim46 2007 English 2002-­2003 598 Peptic ulcer A: TT-­7 ≥80 UBT A: 71.2 A: 83.6 NA A: 5.0
|

B: TT-­14 B: 75.5 B: 86.6 B: 4.6

      5 of 16

(Continues)
T A B L E   1   (Continued)
|

Definition of good Eradication rate, %

6 of 16      

Year of Study Indication of tolerability, % dose Confirmative test Tolerability, Adverse

Author publication Language period Patients eradication Eradication regimen of administration for eradication ITT analysis PP analysis % event, %

Park47 2007 English 2002-­2004 352 Gastric A: TT-­7+probiotics NA UBT A: 83.5 A: 85.5 NA A: 15.3
symptoms B: TT-­7 B: 73.3 B: 78.7 B: 31.8
Choi48 2008 Korean 2007 158 Any A: ST-­10 ≥85 UBT A: 77.9 A: 85.7 A: 100.0 A: 28.6
B: TT-­7 B: 71.6 B: 76.3 B: 100.0 B: 29.6
Kim49 2008 English 2006-­2007 257 Any A: TT-­7 ≥70 UBT A: 72.1 A: 78.8 A: 99.2 A: 21.8
B: TT-­7+mucoprotective B: 78.9 B: 88.6 B: 96.6 B: 20.3
agent
Kim50 2008 English 2006-­2007 347 NA A: TT-­7+probiotics >85 UBT A: 79.2 A: 87.5 A: 98.7 A: 41.1
B: TT-­7 B: 72.1 B: 78.7 B: 99.4 B: 26.3
Kim51 2008 English 2006-­2007 463 Peptic ulcer A: H2RA-­based TT-­7 ≥75 UBT A: 76.5 A: 81.6 A: 97.3 A: 8.7
B: TT-­7 B: 76.9 B: 82.0 B: 96.4 B: 15.4
C: H2RA-­based TT-­14 C: 78.2 C: 82.2 C: 98.2 C: 15.1
D: TT-­14 D: 80.4 D: 85.9 D: 95.3 D: 20.5
Song52 2010 English 2005-­2008 991 Any A: TT-­7 ≥80 UBT A: 71.6 A: 80.1 A: 100.0 A: 19.0
B: TT-­7+probiotics B: 80.0 B: 85.4 B: 99.4 B: 14.5
C: TT-­7+probiotics+muco­ C: 82.1 C: 85.0 C: 99.1 C: 9.1
protective agentc
Choi53 2011 English 2008-­2009 295 Any A: TT-­7 ≥90 UBT A: 77.8 A: 85.6 A: 94.7 A: 55.6
B: TT-­Q-­7 B: 65.3 B: 73.6 B: 96.7 B: 46.0
C: TT-­Q-­7+rifaximin C: 74.5 C: 80.2 C: 96.8 C: 40.7
Kim54 2011 English 2008-­2009 409 Peptic ulcer, A: ST-­10 ≥90 UBT or RUT A: 85.9 A: 92.6 A: 96.8 A: 18.9
gastric MALT B: TT-­14 B: 75.0 B: 85.0 B: 97.2 B: 13.3
lymphoma, or
dyspepsia
Seo55 2011 Korean 2007-­2010 363 Peptic ulcer or A: TT-­7 NA UBT A: 81.4 A: 81.4 A: 100.0 A: 39.7
erosion B: TT-­7+mucoprotective B: 86.2 B: 86.2 B: 100.0 B: 34.6
agent
Choi56 2012 English 2008-­2011 460 Gastritis or A: TT-­7 NA UBT and A: 70.4 A: 75.7 NA A: 9.6
peptic ulcer B: TT-­10 histopathologic B: 74.8 B: 81.9 B: 12.2
C: TT-­14 examination C: 80.0 C: 84.4 C: 10.4
D: ST-­10 D: 75.7 D: 82.1 D: 13.0
Chung57 2012 English 2010-­2011 159 NA A: TT-­10 ≥90 UBT A: 58.8 A: 67.6 A: 95.8 A: 26.3
B: ST-­10 B: 75.9 B: 86.8 B: 95.8 B: 29.1
Kim58 2012 English 2009-­2010 208 Peptic ulcer A: TT-­14 ≥80 UBT A: 74.0 A: 82.8 A: 100.0 A: 35.6
B: DT-­14 B: 67.3 B: 78.4 B: 95.7 B: 18.3

(Continues)
JUNG et al.
T A B L E   1   (Continued)
JUNG et al.

Definition of good Eradication rate, %

Year of Study Indication of tolerability, % dose Confirmative test Tolerability, Adverse
Author publication Language period Patients eradication Eradication regimen of administration for eradication ITT analysis PP analysis % event, %

Oh59 2012 English 2009-­2010 246 Dyspepsia, A: ST-­10 ≥90 UBT A: 79.3 A: 82.0 A: 98.2 A: 27.6
epigastric B: TT-­7 B: 63.1 B: 64.6 B: 99.2 B: 23.8
soreness
Park60 2012 English 2009-­2010 326 NA A: ST-­10 >90 UBT A: 77.8 A: 87.9 A: 92.3 A: 28.0
B: TT-­7 B: 62.2 B: 76.0 B: 91.2 B: 25.5
Kim61 2013 English 2009-­2010 270 NA A: TT-­7 ≥80 UBT, RUT, and A: 72.6 A: 85.2 A: 99.1 A: 25.2
B: CT-­5 histopathologic B: 80.7 B: 91.4 B: 96.7 B: 35.6
examination
Lim62 2013 English 2011-­2012 164 Dyspepsia, A: ST-­14 ≥90 UBT A: 75.6 A: 76.8 A: 97.6 A: 39.5
epigastric B: CT-­14 B: 80.8 B: 81.3 B: 96.2 B: 46.2
soreness
Heo63 2014 English 2012-­2013 348 NA A: CT-­10 ≥90 UBT A: 78.7 A: 88.7 A: 94.9 A: 38.3
B: TT-­10 B: 70.7 B: 78.4 B: 95.6 B: 34.0
Lee64 2014 English 2010-­2013 332 NA A: TT-­7 >85 UBT, RUT, A: 64.3 A: 68.5 A: 100.0 A: 29.6
B: ST-­10 histopathologic B: 72.1 B: 78.4 B: 96.2 B: 31.5
C: ST-­15 examination, or C: 80.2 C: 89.5 C: 97.9 C: 32.1
culture
Oh65 2014 English 2012-­2103 184 NA A: HT-­14 >85 UBT, RUT, or A: 81.1 A: 85.9 A: 98.8 A: 33.7
B: ST-­14 histopathologic B: 79.8 B: 82.0 B: 95.7 B: 39.8
examination
Bang66 2015 English 2012 112 NA A: TT-­7 >85 UBT A: 76.4 A: 87.5 A: 100.0 A: 39.6
B: TT-­7+pronase B: 56.1 B: 68.1 B: 95.7 B: 48.9
Heo67 2015 English 2013-­2014 479 Peptic ulcer, A: CT-­10 >90 UBT A: 78.6 A: 89.8 A: 90.1 A: 38.7d
dyspepsia, B: HT-­10 B: 78.8 B: 89.6 B: 95.0 B: 32.1d
gastric
adenoma or
EGC after
endoscopic
resection
Hwang68 2015 English 2014-­2015 284 NA A: ST-­Q-­14 ≥85 UBT A: 91.4 A: 94.1 A: 100.0 A: 11.8
B: HT-­14 B: 79.2 B: 82.6 B: 100.0 B: 19.6
Hwang69 2015 English 2103-­2014 161 NA A: ST-­Q-­14 >85 UBT A: 91.3 A: 93.6 A: 100.0 A: 12.8
B: ST-­14 B: 71.6 B: 75.3 B: 100.0 B: 24.7
Lee70 2015 English 2013 200 NA A: ST-­10 ≥90 UBT A: 79.0 A: 84.9 A: 93.0 A: 33.3
|

B: ST-­Q-­10 B: 78.0 B: 81.3 B: 96.0 B: 28.6

(Continues)
      7 of 16
T A B L E   1   (Continued)

Definition of good Eradication rate, %

|

Year of Study Indication of tolerability, % dose Confirmative test Tolerability, Adverse

8 of 16      

Author publication Language period Patients eradication Eradication regimen of administration for eradication ITT analysis PP analysis % event, %

Lee71 2015 English 2013-­2014 680 Symptomatic A: TT-­7 >80 UBT A: 64.1 A: 76.2 A: 96.6 A: 36.8
peptic ulcer B: TT-­M-­7 B: 68.8 B: 84.2 B: 92.7 B: 52.2
C: ST-­10 C: 70.0 C: 84.4 C: 95.9 C: 43.8
D: CT-­7 D: 79.4 D: 94.4 D: 96.6 D: 43.7
Chung72 2016 English 2013-­2015 517 Peptic ulcer, A: TT-­10 ≥90 UBT A: 62.6 A: 82.8 A: 95.5 A: 35.1
low-­grade B: ST-­10 B: 70.6 B: 89.5 B: 99.3 B: 32.4
gastric MALT C: CT-­10 C: 77.8 C: 94.4 C: 97.9 C: 39.2
lymphoma,
EGC after
endoscopic
resection
Kim73 2016 English 2011-­2014 601 Peptic ulcer, A: TT-­7 ≥80 UBT A: 70.8 A: 76.9 A: 98.5 A: 43.0
low-­grade B: ST-­10 B: 82.4 B: 88.8 B: 97.2 B: 44.4
gastric MALT
lymphoma,
EGC after
endoscopic
resection
Lee74 2016 English 2014-­2015 390 Any A: ST-­10 >85 UBT, RUT, or A: 74.9 A: 84.2 A: 93.8 A: 47.7
B: BQT-­14 histopathologic B: 68.7 B: 76.5 B: 96.0 B: 36.9
examination
Yoon75 2016 English 2013-­2014 99 NA A: ST-­10 ≥85 UBT A: 58.0 A: 70.0 A: 95.2 A: 26.2
B: ST-­10+NAC B: 67.3 B: 80.5 B: 100.0 B: 26.8
Park76 2017 English 2014-­2015 341 Peptic ulcer, A: ST-­10 ≥90 UBT, RUT, or A: 77.6 A: 91.4 A: 97.3 A: 31.1
low-­grade B: ST-­14 histopathologic B: 73.8 B: 91.0 B: 97.3 B: 45.2
gastric MALT C: CT-­10 examination C: 75.6 C: 95.6 C: 98.7 C: 29.5
lymphoma, D: CT-­14 D: 77.9 D: 98.5 D: 93.6 D: 34.6
EGC after
endoscopic
resection

H2RA-­based TT-­7, H2 receptor antagonist-­based triple therapy for 7 d; H2RA-­based TT-­14, H2 receptor antagonist-­based triple therapy for 14 d; DT-­14, dual therapy for 14 d; TT-­7, conventional triple therapy
for 7 d; TT-­M-­7, metronidazole (or tinidazole)-­containing triple therapy for 7 d; TT-­Q-­7, quinolone-­containing triple therapy for 7 d; TT-­10, conventional triple therapy for 10 d; TT-­14, conventional triple therapy
for 14 d; bismuth-­based TT-­14, bismuth-­based triple therapy for 14 d; bismuth-­based TT-­28, bismuth-­based triple therapy for 28 d; TT-­bismuth-­28, bismuth-­containing triple therapy for 28 d; BQT-­7, bismuth-­
based quadruple therapy for 7 d; BQT-­14, bismuth-­based quadruple therapy for 14 d; ST-­10, sequential therapy for 10 d; ST-­14, sequential therapy for 14 d; ST-­15, sequential therapy for 15 d; ST-­Q-­10,
quinolone-­containing sequential therapy for 10 d; ST-­Q-­14, quinolone-­containing sequential therapy for 14 d; HT-­10, hybrid therapy for 10 d; HT-­14, hybrid therapy for 14 d; CT-­5, concomitant therapy for 5 d;
CT-­7, concomitant therapy for 7 d; CT-­10, concomitant therapy for 10 d; CT-­14, concomitant therapy for 14 d; NAC, N-­acetylcysteine; UBT, urea breath test; RUT, rapid urease test; MALT, mucosa-­associated
lymphoid tissue; EGC, early gastric cancer; ITT, intention-­to-­treat; PP, per protocol; qd, once daily; bid, twice daily; tid, thrice daily; qid, four times in a day; NA, not available.
a
The eradication rate based on the rapid urease test.
b
The eradication rate based on the histopathologic examination.
c
This arm was regarded as the conventional triple therapy with probiotics in the meta-­analysis.
JUNG et al.

d
This value indicates the proportion of patients who showed changes in sense of taste.
JUNG et al.
F I G U R E   2   Evidence network of different eradication regimens. Line represents the comparison between Helicobacter pylori eradication
regimens. Thickness of line represents the number of studies included in each comparison
3.5 | Comparative efficacy of H. pylori
eradication regimens
Because TT-­7 was the most commonly analyzed regimen in the indi-
vidual studies, we showed the comparative efficacy of each eradi-
cation regimen determined based on the eradication rate of TT-­7
through Forest plots (Fig. S3).
Figure S3A shows the efficacy in terms of H. pylori eradica-
tion determined by ITT analysis. Compared to TT-­7, TT-­10 did not
show a superior efficacy (odds ratio [OR] [95% CI]=1.14 [0.84-­
1.55]). Although TT-­14 seemed to have a superior efficacy com-
pared to that of TT-­7, there was no significant difference (OR [95%
CI]=1.23 [0.96-­1.57]). TT-­7 with probiotics (TT-­7+probiotics) had
a superior efficacy compared to that of TT-­7 (OR [95% CI]=1.67
[1.32-­2.11]); however, it required administration of probiotics for
3-­8  weeks.47,50,52 In addition, ST-­10 was superior to TT-­7 in terms
of H. pylori eradication (OR [95% CI]=1.69 [1.42-­2.02]). Moreover,
ST-­10 with N-­acetylcysteine (ST-­10+NAC), ST≥14, ST-­Q-­14,
HT≥10, CT≤7, and CT≥10 showed higher eradication rates than
that of TT-­7.
The comparative efficacy in terms of H. pylori eradication assessed
by PP analysis is shown in Fig. S3B. Overall, the results of the PP anal-
ysis were similar to those of the ITT analysis. Compared to TT-­7, TT-­
7+probiotics, ST-­10, ST-­10+NAC, ST≥14, ST-­Q-­14, HT≥10, CT≤7, and
CT≥10 showed a superior efficacy in terms of H. pylori eradication. In
addition, point estimates, such as ORs, of these regimens were higher
in the PP analysis than in ITT analysis. For example, OR (95% CI) of
ST-­10 in the PP analysis was 2.05 (1.65-­2.54), whereas that in the ITT
analysis was 1.69 (1.42-­2.02).
|
      9 of 16
In terms of tolerability, most regimens were comparable to TT-­7
(Fig. S3C). Metronidazole-­
containing triple therapy for 7 days (TT-­
M-­7) showed a poor tolerability compared to that of TT-­7 (OR [95%
CI]=0.37 [0.15-­0.90]). ST-­10 and CT≥10 tended to be inferior to TT-­7;
however, there was no statistically significant difference (OR [95% CI]:
ST-­10, 0.68 [0.40-­1.16]; CT≥10, 0.51 [0.17-­1.52]).
Table 3 shows comparative efficacy of H. pylori eradication rates in
the major 12 regimens determined by ITT analysis. ST-­10 had a better
eradication rate in ITT analysis than that of TT-­7, TT-­10, and TT-­14
(OR [95% CI]: vs TT-­7, 1.69 [1.42-­2.02]; vs TT-­10, 1.48 [1.12-­1.96]; vs
TT-­14, 1.38 [1.06-­1.80]). ST≥14 also showed a better eradication rate
than TT-­7, TT-­10, and TT-­14 (OR [95% CI]: vs TT-­7, 1.88 [1.29-­2.76];
vs TT-­10, 1.65 [1.10-­2.47]; vs TT-­14, 1.54 [1.00-­2.37]). Additionally,
HT≥10, CT≤7, and CT≥10 had better eradication rates than TT-­7,
­TT-­10, and TT-­14. All the comparative efficacy values among the 21
regimens included in the network meta-­analysis are shown in Table S2
(H. pylori eradication rate in ITT analysis), Table S3 (H. pylori eradication
rate in PP analysis) and Table S4 (tolerability).
Interestingly, ST-­Q-­14 showed a better eradication rate than that
of almost all the other regimens, including ST-­10, ST≥14, HT≥10,
CT≤7, and CT≥10 (OR [95% CI]: vs ST-­10, 3.95 [2.02-­7.75]; vs ST≥14,
3.56 [1.91-­6.62]; vs HT≥10, 3.08 [1.71-­5.53]; vs CT≤7, 3.22 [1.50-­
6.88]; vs CT≥10, 3.17 [1.68-­6.00]), although this regimen was inves-
tigated only in two studies published in 2015.68,69 ST-­Q-­14 included
quinolones, instead of clarithromycin, in the last 7 days of the treat-
ment. In those studies, moxifloxacin-­containing (400 mg once daily)
sequential therapy for 14 days was compared with either hybrid ther-
apy for 14 days (HT-­14) or sequential therapy for 14 days (ST-­14) (OR
[95% CI]: vs HT-­14, 2.81 [1.37-­5.74]; vs ST-­14, 4.14 [1.66-­10.31]).68,69
 |

T A B L E   2   Pooled Helicobacter pylori eradication rate for all included regimens in the meta-­analysis
10 of 16      

ITT analysis PP analysis

Heterogeneity test Heterogeneity test

Pooled eradication rate, Pooled eradication
Regimen Number of studies % (95% CI) Q-­value df P-­value I2 rate, % (95% CI) Q-­value df P-­value I2

H2RA-­based therapy
H2RA-­based TT 1 77.4 (71.5-­82.3) NA NA NA NA 81.9 (75.9-­86.7) NA NA NA NA
H2RA-­based therapy
H2RA-­based TT 1 77.4 (71.5-­82.3) NA NA NA NA 81.9 (75.9-­86.7) NA NA NA NA
Dual therapy
DT-­14 1 67.3 (57.7-­75.6) NA NA NA NA 78.4 (68.6-­85.8) NA NA NA NA
PPI-­based Triple therapy
TT-­7 20 71.1 (68.3-­73.7) 49.6 19 <.001 61.7 78.5 (76.1-­80.8) 39.7 19 .004 52.2
TT-­M-­7 1 68.8 (61.5-­75.3) NA NA NA NA 84.2 (77.1-­89.3) NA NA NA NA
TT-­Q-­7 2 58.7 (45.7-­70.5) 3.9 1 .049 74.2 71.5 (64.7-­77.4) 0.3 1 .566 0.0
TT-­Q-­7+rifaximin 1 74.5 (65.0-­82.1) NA NA NA NA 80.2 (70.8-­87.2) NA NA NA NA
TT-­10 4 67.0 (60.0-­73.4) 8.1 3 .043 63.1 78.4 (72.0-­83.6) 6.7 3 .080 55.5
TT-­14 5 76.4 (73.3-­79.2) 2.5 4 .652 0.0 85.2 (82.4-­87.7) 0.9 4 .929 0.0
TT-­7+probiotics 3 81.1 (78.6-­83.4) 1.1 2 .582 0.0 85.6 (83.2-­87.7) 0.5 2 .767 0.0
TT-­7+mucoprotective agent 2 82.8 (74.4-­88.8) 2.6 1 .106 61.6 87.1 (82.6-­90.6) 0.4 1 .554 0.0
TT-­7+aspirin 1 85.2 (74.0-­92.1) NA NA NA NA 86.7 (75.5-­93.2) NA NA NA NA
TT-­7+pronase 1 56.1 (43.1-­68.4) NA NA NA NA 68.1 (53.6-­79.8) NA NA NA NA
Bismuth-­based quadruple therapy
BQT≥7 2 69.5 (63.7-­74.7) 0.2 1 .644 0.0 80.1 (69.7-­87.6) 2.2 1 .141 54.0
Sequential therapy
ST-­10 14 76.2 (72.8-­79.3) 34.3 13 .001 62.1 85.6 (82.8-­88.0) 27.9 13 .009 53.5
ST-­10+NAC 1 67.3 (53.2-­78.9) NA NA NA NA 80.5 (65.6-­89.9) NA NA NA NA
ST≥14 5 76.3 (72.2-­80.0) 2.8 4 .591 0.0 83.1 (76.0-­88.4) 10.8 4 .029 62.8
ST-­Q-­10 1 78.0 (68.8-­85.1) NA NA NA NA 81.3 (72.2-­87.9) NA NA NA NA
ST-­Q-­14 2 91.4 (86.9-­94.4) 0.0 1 .964 0.0 93.9 (89.8-­96.4) 0.0 1 .876 0.0
Hybrid therapy

(Continues)
JUNG et al.
JUNG et al. |
      11 of 16

Quinolone-­containing sequential therapy for 10 days (ST-­Q-­10)

conventional triple therapy for 7 d with mucoprotective agent; TT-­7+aspirin, conventional triple therapy for 7 d with aspirin; TT-­7+pronase, conventional triple therapy for 7 d with pronase; BQT≥7, bismuth-­
ITT, intention-­to-­treat; PP, per protocol; CI, confidence interval; df, degree of freedom; NA, not applicable; TT-­7, conventional triple therapy for 7 d; H2RA-­based TT, H2 receptor antagonist-­based triple therapy;
DT-­14, dual therapy for 14 d; TT-­M-­7, metronidazole (or tinidazole)-­containing triple therapy for 7 d; TT-­Q-­7, quinolone-­containing triple therapy for 7 d; TT-­Q-­7+rifaximin, quinolone-­containing triple therapy
for 7 d with rifaximin; TT-­10, conventional triple therapy for 10 d; TT-­14, conventional triple therapy for 14 d; TT-­7+probiotics, conventional triple therapy for 7 d with probiotics; TT-­7+mucoprotective agent,

based quadruple therapy for 7-­14 d; ST-­10, sequential therapy for 10 d; ST-­10+NAC, sequential therapy for 10 d with N-­acetylcysteine; ST≥14, sequential therapy for 14-­15 d; ST-­Q-­10, quinolone-­containing
was assessed only in one study published in 2015.70 In this study,

0.0
74.6
41.9

sequential therapy for 10 d; ST-­Q-­14, quinolone-­containing sequential therapy for 14 d; HT≥10, hybrid therapy for 10-­14 d; CT≤7, concomitant therapy for 5-­7 d; CT≥10, concomitant therapy for 10-­14 d.
I2
levofloxacin-­containing (250 mg twice daily) sequential therapy for
10 days was compared with ST-­10 (OR [95% CI]=0.94 [0.48-­1.85]).

P-­value

.003
.179

.344
3.6 | Network heterogeneity and inconsistency
Heterogeneity test

4
2

1
df
In terms of eradication rate, there was no significant heterogeneity in
the whole network (ITT analysis: Cochran’s Q=19.1, df=23, P=.694;
Q-­value

PP analysis: Cochran’s Q=18.8, degrees of freedom [df]=23, P=.711).

0.9
15.7
3.4

No network inconsistency was identified within designs (ITT analysis:

Cochran’s Q=1.6, df=6, P=.955; PP analysis: Cochran’s Q=1.6, df=6,
P=.952), as well as between designs (ITT analysis: Cochran’s Q=17.6,
Pooled eradication

df=17, P=.417; PP analysis: Cochran’s Q=17.2, df=17, P=.440).

91.0 (85.4-­94.6)
86.3 (81.3-­90.1)

92.9 (89.0-­95.5)
rate, % (95% CI)

Regarding the tolerability, there was no significant heterogeneity in

PP analysis

the whole network (Cochran’s Q=10.2, df=18, P=.927), within designs

(Cochran’s Q=1.9, df=5, P=.864), and between designs (Cochran’s
Q=8.3, df=13, P=.826).
0.0
0.0

0.0

3.7 | Ranking of different regimens based on

I2

eradication rate and tolerability

P-­value

.966
.900

.773

Figure 3A shows the P-­score of each regimen for the eradication

rate in ITT analysis against that for tolerability. The P-­score of each
Heterogeneity test

eradication regimen can be interpreted as the mean extent of cer-

df

1
4

tainty that a certain regimen was better than another one.32 P-­scores
of TT-­7 were 23.2% and 64.3% for the eradication rate in ITT analysis
Q-­value

and tolerability, respectively. Generally, sequential and concomitant

0.2

0.1
0.6

therapies showed higher P-­scores for eradication rate and lower P-­
scores for tolerability compared to TT-­7 (eradication rate in ITT analy-
Pooled eradication rate,

sis: ST≥14, 72.5%; ST-­10, 65.4%; CT≥10, 81.3%; and CT≤7, 79.9%;
tolerability: ST≥14, 49.3%; ST-­10, 45.8%; CT≥10, 35.0%; and CT≤7,
79.4 (75.5-­82.8)

80.0 (75.1-­84.1)
78.3 (75.3-­80.9)

48.6%). HT≥10 also showed a higher P-­score for eradication rate

ITT analysis

% (95% CI)

compared to TT-­7 (eradication rate in ITT analysis: 81.4%; tolerability:

68.3%). ST-­Q-­14 showed the highest P-­score for eradication rate with
a relatively good P-­score for tolerability (eradication rate in ITT analy-
sis: 99.8%; tolerability: 55.7%).
Number of studies

In addition, the relation between the P-­scores of eradication rate

in PP analysis and those of tolerability was similar to that between the
P-­scores of eradication rate in ITT analysis and those of tolerability, as
shown in Figure 3B.
3

2
5

4 | DISCUSSION

The Korean guidelines for treatment of H. pylori infections, revised

T A B L E   2   (Continued)

in 2013, recommended the use of the conventional triple therapy

Concomitant therapy

for 7-­14 days as a primary treatment option5 because all other

regimens have not shown superiority over the conventional tri-
ple therapy in terms of H. pylori eradication. However, many
HT≥10

CT≥10

concerns about the insufficient eradication rate of the conven-

Regimen

CT≤7

tional triple therapy have been raised in Korea.11,77 Moreover,

the Maastricht V/Florence Consensus Report stated that
 |
12 of 16      

T A B L E   3   Helicobacter pylori eradication rates in intention-­to-­treat analysis of the major 12 regimens from the network meta-­analysis

Compared regimen, OR (95% CI)

TT-­
Regimen TT-­7 TT-­10 TT-­14 7+probiotics ST-­10 ST-­10+NAC ST≥14 ST-­Q-­10 ST-­Q-­14 HT≥10 CT≤7 CT≥10

TT-­7 — 0.88 0.82 0.60 0.59 0.40 0.53 0.63 0.15 0.46 0.48 0.47
(0.64-­1.19) (0.64-­1.04) (0.47-­0.76) 0.50-­0.70) (0.17-­0.91) (0.36-­0.78) (0.31-­1.26) (0.08-­0.30) (0.29-­0.74) (0.34-­0.68) (0.34-­0.66)
TT-­10 1.14 — 0.93 0.68 0.67 0.45 0.61 0.72 0.17 0.52 0.55 0.54
(0.84-­1.55) (0.65-­1.33) (0.46-­1.00) (0.51-­0.89) (0.19-­1.07) (0.41-­0.91) (0.34-­1.48) (0.09-­0.34) (0.33-­0.83) (0.35-­0.86) (0.40-­0.73)
TT-­14 1.23 1.07 — 0.73 0.72 0.48 0.65 0.77 0.18 0.56 0.59 0.58
(0.96-­1.57) (0.75-­1.54) (0.52-­1.03) (0.56-­0.94) (0.20-­1.15) (0.42-­1.00) (0.37-­1.59) (0.09-­0.37) (0.34-­0.94) (0.39-­0.90) (0.39-­0.85)
TT-­ 1.67 1.47 1.36 — 0.99 0.66 0.89 1.05 0.25 0.77 0.80 0.79
7+probiotics (1.32-­2.11) (1.00-­2.15) (0.97-­1.92) (0.74-­1.32) (0.28-­1.58) (0.57-­1.39) (0.5-­2.19) (0.12-­0.51) (0.45-­1.30) (0.53-­1.22) (0.53-­1.19)
ST-­10 1.69 1.48 1.38 1.01 — 0.67 0.90 1.06 0.25 0.78 0.81 0.80
(1.42-­2.02) (1.12-­1.96) (1.06-­1.80) (0.76-­1.36) (0.29-­1.52) (0.62-­1.29) (0.54-­2.08) (0.13-­0.50) (0.49-­1.23) (0.56-­1.17) (0.59-­1.08)
ST-­10+NAC 2.53 2.22 2.06 1.51 1.49 — 1.34 1.58 0.38 1.16 1.21 1.20
(1.09-­5.85) (0.93-­5.26) (0.87-­4.88) (0.63-­3.61) (0.66-­3.39) (0.55-­3.29) (0.55-­4.58) (0.13-­1.09) (0.46-­2.97) (0.49-­2.98) (0.50-­2.87)
ST≥14 1.88 1.65 1.54 1.13 1.11 0.74 — 1.18 0.28 0.87 0.90 0.89
(1.29-­2.76) (1.10-­2.47) (1.00-­2.37) (0.72-­1.76) (0.77-­1.60) (0.30-­1.83) (0.55-­2.54) (0.15-­0.52) (0.57-­1.32) (0.55-­1.50) (0.63-­1.26)
ST-­Q-­10 1.60 1.40 1.30 0.95 0.94 0.63 0.85 — 0.24 0.73 0.77 0.76
(0.80-­3.21) (0.67-­2.90) (0.63-­2.69) (0.46-­1.99) (0.48-­1.85) (0.22-­1.82) (0.39-­1.82) (0.09-­0.62) (0.33-­1.66) (0.36-­1.65) (0.36-­1.58)
ST-­Q-­14 6.70 5.87 5.46 4.01 3.95 2.65 3.56 4.20 — 3.08 3.22 3.17
(3.38-­13.29) (2.96-­11.64) (2.68-­11.16) (1.94-­8.26) (2.02-­7.75) (0.92-­7.65) (1.91-­6.62) (1.62-­10.88) (1.71-­5.53) (1.50-­6.88) (1.68-­6.00)
HT≥10 2.18 1.91 1.77 1.30 1.28 0.86 1.15 1.36 0.32 — 1.04 1.03
(1.36-­3.49) (1.20-­3.03) (1.06-­2.96) (0.77-­2.20) (0.82-­2.02) (0.34-­2.19) (0.76-­1.76) (0.60-­3.07) (0.18-­0.58) (0.59-­1.86) (0.71-­1.50)
CT≤7 2.08 1.82 1.70 1.25 1.23 0.82 1.11 1.30 0.31 0.96 — 0.99
(1.47-­2.96) (1.16-­2.86) (1.12-­2.59) (0.82-­1.90) (0.85-­1.77) (0.34-­2.02) (0.67-­1.83) (0.61-­2.81) (0.15-­0.66) (0.54-­1.70) (0.62-­1.57)
CT≥10 2.11 1.85 1.72 1.26 1.25 0.84 1.12 1.32 0.32 0.97 1.01 —
(1.52-­2.95) (1.37-­2.49) (1.17-­2.53) (0.84-­1.90) (0.92-­1.69) (0.35-­2.00) (0.80-­1.58) (0.63-­2.77) (0.17-­0.60) (0.67-­1.41) (0.64-­1.62)

OR, odds ratio; CI, confidence interval; TT-­7, conventional triple therapy for 7 d; TT-­10, conventional triple therapy for 10 d; TT-­14, conventional triple therapy for 14 d; TT-­7+probiotics, conventional triple
therapy for 7 d with probiotics; ST-­10, sequential therapy for 10 d; ST-­10+NAC, sequential therapy for 10 d with N-­acetylcysteine; ST≥14, sequential therapy for 14-­15 d; ST-­Q-­10, quinolone-­containing se-
quential therapy for 10 d; ST-­Q-­14, quinolone-­containing sequential therapy for 14 d; HT≥10, hybrid therapy for 10-­14 d; CT≤7, concomitant therapy for 5-­7 d; CT≥10, concomitant therapy for 10-­14 d.
JUNG et al.
JUNG et al. |
      13 of 16

F I G U R E   3   Relationship between the eradication rate and tolerability. (A) ITT analysis, (B) PP analysis. X-­axis represents the P-­score of
each regimen with high eradication rate. Y-­axis represents the P-­score of each regimen with high tolerability. Size of circles and number in the
parentheses represent the number of included studies for each regimen. ITT, intention-­to-­treat; PP, per protocol; H2RA-­based TT, H2 receptor
antagonist-­based triple therapy; DT-­14, dual therapy for 14 d; TT-­7, conventional triple therapy for 7 d; TT-­M-­7, metronidazole (or tinidazole)-­
containing triple therapy for 7 d; TT-­Q-­7, quinolone-­containing triple therapy for 7 d; TT-­Q-­7+rifaximin, quinolone-­containing triple therapy
for 7 d with rifaximin; TT-­10, conventional triple therapy for 10 d; TT-­14, conventional triple therapy for 14 d; TT-­7+probiotics, conventional
triple therapy for 7 d with probiotics; TT-­7+mucoprotective agent, conventional triple therapy for 7 d with mucoprotective agent; TT-­7+aspirin,
conventional triple therapy for 7 d with aspirin; TT-­7+pronase, conventional triple therapy for 7 d with pronase; BQT≥7, bismuth-­based
quadruple therapy for 7-­14 d; ST-­10, sequential therapy for 10 d; ST-­10+NAC, sequential therapy for 10 d with N-­acetylcysteine; ST≥14,
sequential therapy for 14-­15 d; ST-­Q-­10, quinolone-­containing sequential therapy for 10 d; ST-­Q-­14, quinolone-­containing sequential therapy
for 14 d; HT≥10, hybrid therapy for 10-­14 d; CT≤7, concomitant therapy for 5-­7 d; CT≥10, concomitant therapy for 10-­14 d

PPI-­clarithromycin-­containing triple therapy without prior suscep-
tibility testing should be abandoned in the regions where clarithro-
mycin resistance rate is more than 15%.78
Our network meta-­analysis included the recently published stud-
ies after revision of the Korean guidelines. It showed that the con-
ventional triple therapy was inferior to the sequential, hybrid, and
concomitant therapies. Although the tolerability of ST-­10 and ST≥14
tended to be lower than that of TT-­7, it was comparable to that of TT-­
10 and TT-­14. In addition, the tolerability of the hybrid therapy was
comparable to that of TT-­7, TT-­10, and TT-­14. Therefore, it might be
inappropriate to treat H. pylori infections with TT-­10 or TT-­14 rather
than ST-­10, ST≥14, or HT≥10, given that the sequential and hybrid
therapies had better eradication rates than and a comparable tolera-
bility to the conventional triple therapy.
In the previous pairwise meta-­analysis in Korea, sequential ther-
apy was superior to TT-­7 in terms of eradication, while the efficacy
79
did not differ between the sequential therapy vs TT-­10 or TT-­14.
However, these results may be due to the small number of studies
included in the meta-­analysis. Only two studies were included in the
comparisons of either TT-­10 or TT-­14. In our network meta-­analysis,
direct evidence could be combined with indirect evidence. As shown
in Figure 2, there are many indirect comparisons between ST-­10 vs
TT-­10 or TT-­14. The precision of network estimate is usually better
than direct estimate.80 Therefore, we could reveal the superior effi-
cacy of sequential therapy in terms of eradication compared to TT-­10
and TT-­14, as well as TT-­7.
However, the sequential and hybrid therapies as well as con-
ventional triple therapies did not achieve 90% of eradication rate
in the ITT analysis. Among 21 eradication regimens included in the
meta-­analysis, only ST-­Q-­14 showed an acceptable eradication rate
according to the report card to grade H. pylori therapy, proposed by
Graham.81 ST-­Q-­14 showed a significantly higher efficacy in terms of
eradication compared to the most other regimens, including the con-
ventional, sequential, hybrid, and concomitant therapies. Because of
the high resistance rate of H. pylori against clarithromycin in Korea,
it is not surprising that the quinolone-­containing sequential therapy
is more effective than the standard sequential therapy because it
includes quinolone instead of clarithromycin. Based on the results of
the meta-­analysis, ST-­Q-­14 may be considered as a primary treatment
option for H. pylori infections in Korea. However, there are several
concerns regarding this regimen. First, the number of studies on the
quinolone-­containing sequential therapy is relatively small. Second,
the quinolone-­containing sequential therapy was not directly com-
pared with the conventional triple therapy. It was compared with
either the standard sequential therapy or hybrid therapy. In other
words, superiority of the quinolone-­
containing sequential therapy
 |
14 of 16       JUNG et al.
over the conventional triple therapy was proven by indirect evidence
only.
On the other hand, there were several regimens including addi-
tive drugs, such as probiotics and mucoprotective agents. These
regimens were devised as an effort to improve the efficacy of TT-­7.
Unfortunately, they showed a less tolerability than TT-­7, the sequen-
tial and concomitant therapies. Although TT-­7+probiotics was superior
to TT-­7 in terms of eradication rate, prolonged administration of pro-
biotics for 3-­8 weeks may be a drawback of the probiotic-­containing
regimens.
In addition, our study showed the trend of the studies on H. pylori
eradication during the last 20 years. The conventional triple therapy
was the most widely investigated regimen in Korea, and it was con-
sidered the reference regimen for evaluation of alternative regimens
in recent years. The efficacy of the standard sequential therapies,
including ST-­10 and ST≥14, was analyzed since 2008. The concom-
itant therapies, including CT≤7 and CT≥10, were evaluated since
2013. More recently, the quinolone-­containing sequential therapy
was studied in 2015. These alternative regimens usually showed a
superior efficacy in terms of eradication rate compared to the con-
ventional triple therapy. Among the alternative regimens, ST-­10 was
supported by the largest number of individual studies. Although ST-­
Q-­14 was investigated in two studies only, it should be considered
because it showed the highest eradication rate and a good tolerability
as mentioned above.
Although this study represents the first network meta-­analysis
to compare the efficacy of various H. pylori eradication regimens
in Korea, it has several limitations. First, there was a lack of direct
evidence in several comparisons because several major regimens,
such as TT-­7 and ST-­10, were used as references. However, most
of the individual studies were designed to compare the regimens of
interest with each other; therefore, most of the comparisons had
direct estimates. Second, susceptibility testing was not considered
in our network meta-­analysis. Although susceptibility testing is a
strong method for choosing the optimal eradication regimen for
each patient, it was not used in most Korean studies. The results
of our network meta-­analysis should be used only when the eradi-
cation therapy will be planned without prior susceptibility testing.
Despite these limitations, our network meta-­analysis provides a
better understanding of the efficacy of various first-­line eradication
regimens in Korea. Both sequential and hybrid therapies had a supe-
rior efficacy in terms of eradication rate and a comparable tolerability,
compared to the results reported for the conventional triple thera-
pies, including TT-­7, TT-­10, and TT-­14. However, they did not achieve
90% of eradication rate in the ITT analysis. Only ST-­Q-­14 showed
an acceptable eradication rate with a good tolerability among the 21
included regimens in Korea; however, more studies on this regimen are
required for reaching a definitive conclusion.
ACKNOWLE DG E MEN TS A N D DI SCLO SURE S
CO MPE TI NG I NTE RE STS
The authors have no competing interests.
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(“1990/01/01”[Date -­Publication] : “2016/11/30”[Date -­Publication])
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py AND [embase]/lim
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S U P P O RT I NG I NFO R M AT I O N
Additional Supporting Information may be found online in the sup-
porting information tab for this article. 
How to cite this article: Jung YS, Park CH, Park JH, Nam E, Lee
HL. Efficacy of Helicobacter pylori eradication therapies in Korea:
A systematic review and network meta-­analysis. Helicobacter.
2017;00:e12389. https://doi.org/10.1111/hel.12389
Cochrane library
1. helicobacter:ab,ti or campylobacter:ab,ti or pylori*:ab,ti
2. eradication:ab,ti or treatment:ab,ti
3. korea*
4. #1 and #2 and #3 (Publication Year from 1990 to 2016)
KoreaMed
1. helicobacter and eradication
2. helicobacter and treatment
3. campylobacter and eradication
4. campylobacter and treatment
5. pylori and eradication
6. pylori and treatment
7. #1 or #2 or #3 or #4 or #5 or #6 (Publication Year from 1990 to 2016)