First-Line Helicobacter Pylori Eradication Therapies in Countries

Helicobacter pylori

ORIGINAL ARTICLE Gut: first published as 10.1136/gutjnl-2016-311868 on 26 September 2016. Downloaded from First-line Helicobacter pylori eradication therapies in countries with high and low clarithromycin resistance: a systematic review and network meta-analysis Yee Hui Yeo,1,2 Sz-Iuan Shiu,1 Hsiu J Ho,1 Biyao Zou,3 Jaw-Town Lin,4,5 Ming-Shiang Wu,6 Jyh-Ming Liou,6 Chun-Ying Wu,1,6,8,9,10 Taiwan Gastrointestinal Disease and Helicobacter Consortium

►► Additional material is ABSTRACT published online only. To view Objective To determine the optimal regimen of Significance of this study please visit the journal online fi (http://dx.doi.org/10.1136/ different rst-line Helicobacter pylori eradication gutjnl-2016-311868). therapies according to the clarithromycin resistance rate. Design Electronic search for articles published between What is already known on this subject? For numbered affiliations see ▸ end of article. January 2005 and April 2016. Randomised, controlled Eradication rate of conventional triple therapy trials that reported the effectiveness of first-line has declined progressively worldwide, Correspondence to eradication therapies in treatment-naïve adults were particularly in clarithromycin-based triple Professor Chun-Ying Wu, included. Two independent reviewers performed articles therapy. Division of Gastroenterology screening and data extraction. Network and traditional ▸ Several regimens such as concomitant therapy, and Hepatology, Taichung meta-analyses were conducted using the random effect sequential therapy and hybrid therapy have Veterans General Hospital 1650, Sec. 4, Taiwan Boulevard, model. Subgroup analyses were performed to determine been proposed to improve the eradication rate. the ranking of regimens in countries with high (>15%) Taichung 40705, Taiwan; fi chun@vghtc.gov.tw and low (<15%) clarithromycin resistance. Data What are the new ndings? including adverse events and therapeutic cure rate were ▸ Overall, sequential therapy for 14 days Received 15 March 2016 also extracted and analysed. presented the highest eradication rates. Revised 1 September 2016 ▸ Sequential therapy and hybrid therapy Accepted 2 September 2016 Results 117 trials (totally 32 852 patients) for 17 Published Online First H. pylori eradication regimens were eligible for inclusion. appeared to be the most effective therapies in 26 September 2016 areas with high and low clarithromycin Compared with 7-day clarithromycin-based triple therapy, http://gut.bmj.com/ sequential therapy (ST) for 14 days had the highest resistance, respectively. effectiveness (OR=3.74, 95% CrI 2.37 to 5.96). ST-14 ▸ Longer duration was associated with increased (OR=6.53, 95% CrI 3.23 to 13.63) and hybrid therapy effectiveness, and also with higher risk of (HY) for 10 days or more (OR=2.85, 95% CrI 1.58 to events that lead to discontinuation. 5.37) represented the most effective regimen in areas How might it impact on clinical practice in with high and low clarithromycin resistance, respectively. the foreseeable future? The effectiveness of standard triple therapy was below ▸ Our report presented evidence-based hierarchy on September 30, 2021 by guest. Protected copyright. therapeutic eradication rate in most of the countries. Longer for the effectiveness of 17 eradication regimens duration was associated with higher eradication rate, but according to clarithromycin resistance rate. with a higher risk of events that lead to discontinuation. ▸ Our report provides significant insights into the Conclusions ST and HY appeared to be the most compositional effects of regimen type and effective therapies in countries with high and low duration, adverse events and therapeutic cure clarithromycin resistance, respectively. The clinical rate to facilitate physician’s decision-making decision for optimal regimen can be supported by fi process respecting optimal regimen selection referring to the rank ordering of relative ef cacies and treatment duration. stratified by local eradication rates, antibiotic resistance and safety profile. Trial registration number CRD42015025445.

three-quarter of all gastric cancer cases.23The eradication of H. pylori has been recommended in patients with long-term use of non-steroidal anti- INTRODUCTION inﬂammatory drugs (NSAIDs), antiplatelet agent or Helicobacter pylori infection is present in more low-dose aspirin, as well as for patients with unex- than half of the population worldwide.1 It is caus- plained iron-deﬁciency anaemia or idiopathic ally associated with the pathogenesis of peptic ulcer thrombocytopenic purpura to improve the patients’ 4 To cite: Yeo YH, Shiu S-I, disease, active gastroduodenal ulcer bleeding, prognosis. Ho HJ, et al. Gut gastric mucosa-associated lymphoid tissue Standard triple therapy (TT), which consists of 2017;67:20–27. lymphoma, and is accountable for more than proton pump inhibitor (PPI), amoxicillin,

20 Yeo YH, et al. Gut 2017;67:20–27. doi:10.1136/gutjnl-2016-311868 Helicobacter pylori

clarithromycin or metronidazole, was developed in the 1990s examination, bacterial culture, rapid urea test or stool antigen Gut: first published as 10.1136/gutjnl-2016-311868 on 26 September 2016. Downloaded from and recommended as the first-line eradication therapy due to detection). Eligible reports were those that compared two or favourable eradication rate initially. In recent years, mounting more of the 17 studied regimens. H. pylori eradication rate was evidence has indicated progressively declining eradication rate determined by intention to treat analysis at least 4 weeks after – for TT.5 7 Alternative combination regimens have been pro- completion of eradication regimen. Studies of paediatric patients posed, including bismuth-containing quadruple therapy (BQT), or patients with severe comorbidities were excluded, as were non-bismuth quadruple therapy (also called concomitant those that included probiotics, H2 blockers and herbs. therapy, CT), sequential therapy (ST), hybrid therapy (HY) and Two investigators checked titles, abstracts and full texts inde- quinolone-based TT. Their efficiencies have been tested in dif- pendently to clarify the eligibility of each article. All discrepan- ferent countries, including countries with high or low clarithro- cies were discussed and resolved in consultation with a third mycin resistance. However, the optimal regimen for H. pylori investigator. Non-English articles were translated when needed. eradication remains elusive. Moreover, there is little evidence on We attempted to contact investigators to acquire full text or to the therapeutic eradication rate (higher than 80%48) of differ- clarify and obtain study results. Finally, articles without full text ent regimens in different countries. available from the authors and abstracts from conferences were In search of the optimal eradication therapy, systematic excluded. reviews have focused on the relative effectiveness of standard TT compared with the newer regimens. However, comparative Data extraction and quality assessment studies of new regimens are still limited. There are two major The following variables were extracted by two investigators obstacles to conducting traditional meta-analyses for compari- independently: participant demographic characteristics, methods sons of multiple regimens. The first is the difficulty in applying for detecting H. pylori infection, details of regimens, the conventional pairwise meta-analyses to the integration and sys- washout period of antibiotics, PPIs, aspirin, use of NSAIDs, tematic comparison of more than two eradication regimens. The eradication rates and methods and time points for detecting second is that not all of the eradication regimens have been H. pylori eradication. We also derived compliance rates, severe compared head-to-head via randomised controlled trial (RCT). adverse events and events that were responsible for drugs dis- Network meta-analysis can be used to investigate several treat- continuation from included studies. ment comparators simultaneously with direct and indirect com- We grouped the 17 included regimens according to clinical – parisons.9 11 Li and colleagues recently reported a network similarity: clarithromycin-based triple therapy for 7 days meta-analysis to explore the most efficacious therapy for eradi- (TT-C-7), clarithromycin-based triple therapy for 10 days cation of H. pylori.12 However, the inclusion of early papers, (TT-C-10), clarithromycin-based triple therapy for 14 days incomplete inclusion of trials and the comparison of non- (TT-C-14), quinolone-based triple therapy for 7 days (TT-Q-7), mainstream regimens such as probiotics and H2 blocker con- quinolone-based triple therapy for more than or equal to taining therapies may result in higher heterogeneity and 10 days (TT-Q≥10), metronidazole-based triple therapy for inconsistency. 7 days (TT-M-7), metronidazole-based triple therapy for more In the present study, we conduct network meta-analysis to than or equal to 10 days (TT-M≥10), triple therapy with two compare the relative efficacies and tolerabilities of 17 key regi- major drugs (PPI+quinolone+clarithromycin or quinolone http://gut.bmj.com/ mens in the eradication of H. pylori to determine the most +metronidazole) for 7 days (TT-D-7), bismuth-containing quad- favourable regimens for treatment-naïve patients. To enhance ruple therapy (bismuth+PPI+tetracycline+metronidazole) for the clinical significance, we performed subgroup analysis to less than or equal to 10 days (BQT≤10), bismuth-containing determine the rank ordering of regimens in countries with high quadruple therapy for 14 days (BQT-14), modified bismuth- (>15%) and low (<15%) clarithromycin resistance. We also containing quadruple therapy (bismuth+PPI+any two of conducted a systematic review to explore the severe adverse amoxicillin/tetracycline/metronidazole/clarithromycin) for less ≤ fi event rates and the weighted eradication rate of different therap- than or equal to 10 days (mBQT 10), modi ed bismuth- on September 30, 2021 by guest. Protected copyright. ies in each study country. containing quadruple therapy for 14 days (mBQT-14), concomitant therapy for less than or equal to 7 days (CT≤7), concomi- MATERIALS AND METHODS tant therapy for more than or equal to 10 days (CT≥10), Data sources and searches sequential therapy for less than or equal to 10 days (ST≤10), We searched PubMed and Cochrane Central Register of sequential therapy for 14 days (ST-14) and hybrid therapy for Controlled Trials to identify relevant trials without language more than or equal to 10 days (HY≥10). restriction. Detailed search strategies are described in the online We explored the comparison network of relative estimated supplementary appendix 1. We also scanned the reference lists effects by drawing geometry of 17 regimens. In the network of of reviews and included studies for additional trials. Antibiotic regimens, each regimen is presented as a node. The lines resistance may rise incrementally and impose bias. Similar to a between any two nodes represent studies comparing two linked recent consensus, we restricted our search to full-text articles treatments. published from 2005 to 2016 April.13 The preplanned protocol Two authors independently evaluated the risk of bias of all of our network meta-analysis is documented online studies based on the Cochrane Handbook for Systematic (PROSPERO registry-CRD42015025445). The study protocol Reviews of Interventions,14 with disagreements resolved was approved by the institutional review boards of Taichung through consensus. Our report was conducted based on the Veterans General Hospital. PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of healthcare interventions Study selection (see online supplementary table S5).15 We included RCTs for the evaluation of H. pylori eradication rate in treatment-naïve adults (aged 18 years or older) with a Data synthesis and analysis diagnosis of H. pylori infection according to one or more of the First, we conducted traditional pairwise meta-analyses with standard detection methods (13C-urea breath test, histological random effects models for all regimens compared within the

Yeo YH, et al. Gut 2017;67:20–27. doi:10.1136/gutjnl-2016-311868 21 Helicobacter pylori

included studies using R software. On DerSimonian and Laird excluded due to duplication, non-RCT, unavailability of full text, Gut: first published as 10.1136/gutjnl-2016-311868 on 26 September 2016. Downloaded from random effects models, we calculated the pooled estimates of ineligible study design, employment of therapy other than the 17 ORs and 95% CIs of direct comparisons between any two of study H. pylori eradication therapies and comparison of different the studied regimens.16 PPIs or bismuth. Finally, 117 studies were eligible for inclusion in Heterogeneity of treatment effects among included studies the network meta-analysis. was examined using the Cochrane Q test and I2 statistic. I2 of The major characteristics of the included RCTs are listed in 25%, 50% and 75% represent low, moderate and high hetero- the online supplementary appendix 1 table S1. In total, 32 852 geneity.17 We checked for publication bias using Egger’s regres- treatment-naïve participants were recruited. The mean age of sion asymmetry test. For Cochrane Q test and Egger’s test, a these patients was 47.75. The total number of participant in two-sided p value of <0.05 was regarded as significant. We also each trial ranged from 59 to 1463. The mean sample size for performed netfunnel plot to examine the publication bias.18 each trial was 280.56 subjects. Most studies assessed H. pylori Second, we conducted network meta-analysis in a Bayesian infection status at 4–12 weeks after the completion of therapy, – framework.9 11 WinBUGS software V.1.4.3 (MRC Biostatistics except one trial that detects outcome at 14 weeks. We con- Unit, Cambridge, UK) was used for estimation of effect sizes ducted internal validity assessment for each study included with non-informative priors. We adopted random effects models in the meta-analysis (see online supplementary appendix 1 due to the nature of network meta-analysis, which comprises figure S1). Inadequate allocation concealment was the main tolerability to between-study heterogeneity and within-study source of potential bias in our meta-analysis. variability. Posterior distributions of model parameters were The network of comparison of the 17 therapies is described assessed based on three sets of initial values and 300 000 itera- in figure 2. In total, 117 studies comprising 266 comparison tions (100 000 per chain). For each chain, we discarded the first arms were enrolled. Figure 3 summarises the pooled estimates 25 000 estimates as the burn-in period. A thinning interval of of the results of network meta-analysis for the effectiveness of 10 was used to fit the model. Convergence of iterations was H. pylori eradication. Among all of the therapies, ST-14 conducted by adopting the Gelman-Rubin-Brooks statistic. Lack (OR=3.74, 95% CrI 2.37 to 5.96) presented the highest effica- of autocorrelation was confirmed for all iterations. We derived cies. These were followed by HY≥10 (OR=2.94, 95% CrI 1.93 the median of posterior distributions and 95% credible interval to 4.49), mBQT-14 (OR=2.87, 95% CrI 1.61 to 5.17), CT≥10 (CrI) (2.5%–97.5% percentile) to determine the point estimate (OR=2.80, 95% CrI 2.07 to 3.82), BQT-14 (OR=2.64, 95% and distribution of treatment effect. CrI 1.21 to 5.78), BQT≤10 (OR=2.60, 95% CrI 1.75 to 3.87), The assumption of transitivity implicates the distribution of TT-Q≥10 (OR=2.31, 95% CrI 1.52 to 3.53), CT≤7 effect modifiers is the same in all pairwise comparisons. The (OR=2.08, 95% CrI 1.51 to 2.91) and ST≤10 (OR=2.04, 95% potential effect modifiers in our study include age, smoking CrI 1.68 to 2.49) all of which were at least two times more status and drug adherence. Violation of transitivity would be effective than TT-C-7. TT-M-7 (OR=0.82, 95% CrI 0.56 to suggested if there was inconsistency between direct and indirect 1.19) represented the least efficacious regimen among all results.19 Inconsistency is defined as the difference between regimens. direct and indirect evidence for each linked comparison in the Regimens of longer duration tended to demonstrate higher network. We evaluated the differences by estimating concord- effectiveness when compared with regimens of shorter duration http://gut.bmj.com/ ance within closed loops using R software.20 We further (figure 4). The OR for the comparison between ST-14 and checked clinical and methodological variables to search for ST≤10 was 1.84 (95% CrI 1.17 to 2.90). Longer duration of potential reasons that contribute to inconsistency. quinolone-based triple therapy (TT-Q≥10) was superior to shorter duration of quinolone-based triple therapy (TT-Q-7), Additional analyses with OR of 1.91 (95% CrI 1.23 to 2.96). TT-C-14 (OR=1.72, To enhance the clinical applicability of our report, we 95% CrI 1.37 to 2.17) and TT-C-10 (OR=1.32, 95% CrI 1.04

performed subgroup analyses to investigate the rank ordering of to 1.69) presented higher eradication rate when compared with on September 30, 2021 by guest. Protected copyright. H. pylori eradication regimens among countries with high and TT-C-7. The effectiveness of most triple therapies was inferior low clarithromycin resistance. We performed a literature review to alternative regimens such as quadruple therapy, ST, CT and to determine the prevalence of clarithromycin resistance of HY. countries where RCTs were conducted from literature published We also categorised included studies into two groups accord- in the last 10 years. Accordingly, all included RCTs were cate- ing to the resistance rate to clarithromycin in the respective gorised into high or low clarithromycin resistant group using countries (see online supplementary appendix 2 table S1). resistant rate of 15% as cut-off. The rank of each treatment was Among included studies, 76 trials were classified into ‘high- determined in both groups. Besides, we examined weighted clarithromycin resistance group’ while 36 trials were categorised average eradication rates for all regimens in each country. The into ‘low-clarithromycin resistant group’. In the former group, results were categorised by clarithromycin resistance rate. ST-14 (OR=6.53, 95% CrI 3.23 to 13.63) revealed the highest Providing that antibiotic resistant rate increases over time and efficacies, followed by BQT≤10 (OR=3.64, 95% CrI 2.07 to may cause bias to the results, we categorised all RCTs into 6.48), BQT-14 (OR=3.49, 95% CrI 1.48 to 8.30) and 2005–2010 and 2011–2016 and investigated the relative effica- mBQT-14 (OR=3.33, 95% CrI 1.79 to 6.29). Among countries cies of regimens in both subgroups. Furthermore, we conducted with low clarithromycin resistance, HY≥10 (OR=2.85, 95% sensitivity test by omitting studies with one or more treatment CrI 1.58 to 5.37) presented highest OR, followed by CT≥10 arms of <50 patients, high heterogeneity and reporting bias as (OR=2.43, 95% CrI 1.55 to 3.88) and ST-14 (OR=2.24, 95% they might substantially affect the results.21 CrI 1.29 to 3.93) (online supplementary appendix 2 table S2a, S2b). We reviewed all included trials and calculated the average RESULTS eradication rate weighted by the number of participants (see We initially identified 7130 citations from the literature online supplementary appendix 1 table S2). When compared (figure 1). Of these, we excluded 6835 articles after the title and with other regimens, 7-day triple therapies achieved therapeutic abstract screening. Of the remaining 295 articles, 178 were rate in few countries. In addition, countries such as Turkey that

22 Yeo YH, et al. Gut 2017;67:20–27. doi:10.1136/gutjnl-2016-311868 Helicobacter pylori

Figure 1 Literature search and Gut: first published as 10.1136/gutjnl-2016-311868 on 26 September 2016. Downloaded from selection ﬂow diagram. http://gut.bmj.com/ on September 30, 2021 by guest. Protected copyright.

presented low eradication rate in most triple therapies should ranked low in both 2011–2016 category and 2005–2010 cat- consider more advanced therapies as first-line treatment. egory. Sensitivity analyses demonstrated that omissions of Acknowledging that resistant rate increase over time, we also studies with low numbers of patients in treatment arms and performed subgroup analysis based on of publication year (see reporting bias only minimally affected on the rank ordering of online supplementary figure S2). ST-14 was ranked the first and the 17 regimens (see online supplementary table S3). However, second place in 2005–2010 and 2011–2016 subgroups, respect- BQT emerged as top three regimens in the effectiveness ranking ively. The rank of mBQT-14 rose from sixth in 2005–2010 when trials with high heterogeneity were excluded. group to first in 2011–2016 group. However, this results needs Estimations of pooled ORs for H. pylori eradication by trad- to be interpreted in cautious, as there was only one trial that itional meta-analysis, heterogeneity analyses and publication bias compared mBQT-14 in 2005–2010 group. Most triple therapies are illustrated (see online supplementary figure S3). Overall, the

Yeo YH, et al. Gut 2017;67:20–27. doi:10.1136/gutjnl-2016-311868 23 Helicobacter pylori Gut: first published as 10.1136/gutjnl-2016-311868 on 26 September 2016. Downloaded from

Figure 2 Network of comparisons for Bayesian meta-analysis. Each circle represents an included regimen. The area of each of the circles is proportional to the number of subjects who received the regimen (numbers of subjects are shown below the regimens). Each line denotes direct comparison between two regimens. The width of the connecting lines is proportional to the number of trials (1–17). The abbreviations of the 17 regimens are listed next to the ﬁgure.

Figure 3 Order of ORs for Helicobacter pylori eradicative regimens. The forest plot illustrates the rank order of all comparators according to their efﬁcacies. CrI denotes credible interval. The abbreviations of the regimens are listed in ﬁgure 2. http://gut.bmj.com/ on September 30, 2021 by guest. Protected copyright.

majority of comparisons yielded moderate to severe heterogen- (longer or equal to 10 days) were associated with higher rate of eity. According to inconsistency analysis, inconsistency was events that lead to discontinuation. observed in only a few cases: 15 of the total 83 loops (see online supplementary figure S4). Of note, loops that present DISCUSSION inconsistencies were constituted of comparisons that comprised In the present study, we systematically compared 17 major regi- very few trials. Therefore, the extent of inconsistency did not mens for H. pylori eradication to determine the optimal treat- seem profound enough to impact the effect size of the estimates. ment for treatment-naïve patients. We demonstrated the highest Regarding publication bias, visual inspection of our netfunnel eradication efficacies for ST-14 in countries with high clarithro- plot did not reveal marked asymmetry (see online supplemen- mycin resistance and HY≥10 in countries with low clarithromy- tary figure S5). cin resistance. We found that regimens of longer duration tend We also reviewed severe adverse events or events that lead to to have higher effectiveness than regimens of shorter duration. withdrawal (see online supplementary table S4). Severe adverse Besides, conventional regimens showed lower effectiveness than events were rare for all regimens. Events that lead to discontinu- alternative regimens. Higher risk of events that lead to with- ation were observed in 57 trials. Regimens with longer duration drawal was observed in regimens of longer duration. The

24 Yeo YH, et al. Gut 2017;67:20–27. doi:10.1136/gutjnl-2016-311868 Helicobacter pylori Gut: first published as 10.1136/gutjnl-2016-311868 on 26 September 2016. Downloaded from

Figure 4 Comparative efficacies of Helicobacter pylori eradication regimens by league table. Left lower: the row-defining regimens are compared with the column-defining regimens by network meta-analyses. OR of more than one reflects increased effectiveness by the row-defining regimens. For example, the cell at the intersection of column 1 and row 3 indicates that the eradication rate of clarithromycin-based triple therapy for 14 days (TT-C-14) is significantly higher than that of clarithromycin-based triple therapy for 7 days (TT-C-7) with OR=1.72 (95% CrI 1.37 to 2.17). Right upper: the column-defining regimens are compared with the row-defining regimens by traditional meta-analyses. Cells with red and pink background denote ORs significantly higher than 2.00 and range between 1.01 and 1.99, respectively. Cells with dark blue and light blue backgrounds denote ORs significantly lower than 0.50 and range between 0.99 and 0.51, respectively. Cells with grey backgrounds denote ORs with http://gut.bmj.com/ non-significant difference. The abbreviations of the regimens are listed in figure 2. CrI, credible interval. therapeutic eradication rate according to clarithromycin resist- eradication. In previous network meta-analyses, therapies were ance rate also provided clinically meaningful information for grouped into three comparators22 23 or 14 comparators.12 decision-making. Taken together, our study presents comprehen- Although the latter comprehensively compared estimated effects sive comparisons of H. pylori eradication therapies according to of different regimens, the authors included different kinds of on September 30, 2021 by guest. Protected copyright. clarithromycin resistance rate and provides significant insights probiotics-containing and H2 blockers-containing regimens in into the compositional effects of regimen type and duration, the network. Moreover, they grouped clarithromycin-based adverse events and therapeutic cure rate. therapy with metronidazole-based therapy, which might not Using Bayesian network meta-analysis, which integrates the provide crucial clinical information to clinicians. The results advantages of direct and indirect evidence, we were able to obtain that the effectiveness of probiotics-supplemented TT was signifi- more accurate estimations. In contrast to traditional meta-analysis, cantly greater than 14 days HY and 10 or 14 days ST were not network meta-analysis allows for the simultaneous assessment of comparable to clinical observations. more than two types of interventions. Furthermore, it provides The results of the present study that longer duration increases estimates of comparative effect among all regimens, including eradication rate are consistent with the findings of previous ana- those that have not been compared head-to-head in the literature. lyses. Yuan et al reported that prolonged duration of PPI-based TT Moreover, the large pooled patient size contributed substantial significantly increases eradication rate.24 In the present guidelines, statistical advantage by enhancing the power of our study, as well it is suggested that the duration of clarithromycin-based TT be as to the robustness of our analyses. As the geometry provides a extended as previous meta-analyses have indicated that 10-day and nice graphical overview of the proportion of participants in differ- 14-day treatment regimens improve H. pylori eradication rate – ent regimens and where the gaps were, the authors were well when compared with 7-day treatment regimen.42527 According placed to propose research priorities. According to a recent con- to World Gastroenterology Organisation global guidelines for low- sensus, inclusion of earlier literature, when antibiotic resistance income and middle-income countries, however, an optimal dur- rate was low, could introduce bias.13 Therefore, we only included ation for H. pylori eradication remains controversial. Taking into articles from 2005 onwards. consideration local clarithromycin resistance, cost-effectiveness To our knowledge, this is the most comprehensive network and compliance, some research groups have suggested 7-day treat- meta-analysis of RCTs in assessing optimal therapy for H. pylori ment while some have favoured 10-day therapy.1

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The superiority of newly developed regimens, such as ST, CT included studies. Studies that were published after 2005 in pre- Gut: first published as 10.1136/gutjnl-2016-311868 on 26 September 2016. Downloaded from and HY, has been confirmed in the present study. ST was devel- vious meta-analysis supported that CT≥10 had higher effective- oped in Italy in 2000.28 Previous meta-analyses reported that ness than TT-C≥10.45 46 In addition, we showed that BQTs ST demonstrated higher effectiveness than TT.29 30 Since most presented high relative efficacies in high clarithromycin resist- clinical trials of ST enrolled in our meta-analyses have been con- ance group. This is consistent to previous studies that clarithro- ducted in Italy, Asia-Pacific consensus guidelines in 2009 sug- mycin resistance does not influence the effectiveness of gested that more evidence is needed to support ST as an BQT.44 47 alternative to clarithromycin-based TT in Asian countries.31 A key assumption of network meta-analysis is the transitivity Recently, three meta-analyses from Asia comparing the efficacies between trials.48 The baseline characteristics and potential effect of ST and standard TT have shown significant but modest modifiers seemed broadly similar across regimens. However, we – increase in eradication rate following ST.32 34 In a recent were not able to explore the distribution of smokers because meta-analysis, 10-day ST is superior to 7-day TT (relative risk many studies that did not report on this. Although certain (RR) 1.21, 95% CI 1.17 to 1.25), marginally superior to 10-day extent of clinical heterogeneity is unavoidable, we have tried to TT (RR 1.11, 95% CI 1.04 to 1.19) and inferior to 14-day TT minimise the effect by using strict inclusion criteria and exclud- (RR 1.00, 95% CI 0.94 to 1.06).35 Our results showed that ing articles that were published before 2005. both ST-14 and ST≤10 are superior to all 7-day, 10-day and There are several limitations to the present study. First, we only 14-day TT, with the exception that TT-Q≥10 demonstrated investigated mainstream eradication regimens in treatment-naïve higher effectiveness than ST≤10. Among countries with high patients. Non-mainstream regimens (eg, furazolidone-based clarithromycin resistance, the OR of ST-14 rose substantially to regimen) were thus not included in this study. Second, inadequate 6.53 (95% CrI 3.23 to 13.63), while the rank of ST-14 dropped concealment and blinding may elicit bias and impact the size of the to third place among countries with low clarithromycin resist- estimate. Subgroup analysis to detect the effect of inadequate con- ance. The use of ST as first-line therapy is in line with two cealment was not performed because less than half (44 studies) of guidelines,436but challenges the other one.13 Therefore, the the included studies reported adequate concealment. Third, the use of optimal regimen requires other considerations such as overall heterogeneity in this network meta-analysis was moderate local antibiotic resistance and cost. Besides, it is 10-day but not to severe. Excluding studies with high heterogeneity influenced 14-day ST being recommended in current guidelines. Since the ranking of regimens, which might due to fewer studies in some there were only five trials that compared ST-14, all of which pairwise comparisons. Fourth, although inconsistency is low in were from Asian countries, more trials are needed in order to our study, there is no sufficient evidence to prove that this is the yield a confirmed conclusion. conclusive evidence of network consistency. This is owing to the CT is less complex than ST and HY with the administration random effect model used in our study and the moderate level of of four drugs at the same time.37 38 From a meta-analysis of six between-study heterogeneity. Finally, synthesis of evidence under clinical trials, most of which were published before 2001, the the condition of multiple comparisons may mitigate homogeneity effectiveness of CT is higher than that of standard therapy (OR and thereby affect further interpretation. We enrolled RCTs from 2.40, 95% CI 1.63 to 3.55).39 On the contrary, Greenberg et al the recent 10 years to avoid potential bias posed by increasing published one large trial in seven Latin American sites and con- resistance rate with the aid of washout period and outcome meas- http://gut.bmj.com/ cluded that 5-day CT is inferior to 14-day clarithromycin-based urement to enhance the homogeneity of included trials. TT.40 Therefore, it has been suggested that elevated antibiotic In conclusion, ST and HY appeared to be the most effective resistance impedes the success of 5-day CT and that longer treat- therapies in countries with high and low clarithromycin resist- ment duration is warranted.39 The results of the present ance, respectively. Our network meta-analysis provides practical network meta-analysis support this hypothesis, as we find that implications that may be translated into clinical benefit. The CT≥10 is more effective than all TT. The eradication effect of rank order, when interpreted concerning different local antibio- ≥ fi CT 10 was ranked as the fth and second choice in countries tics resistant rates, tolerability and local therapeutic rate, may on September 30, 2021 by guest. Protected copyright. with high and low clarithromycin resistance, respectively. help physicians in determining favourable first-line therapy HY was first proposed in 2011, and its effectiveness has been regimen and duration for H. pylori eradication. compared with ST and CT.41 Two meta-analyses have suggested similar eradication rates for these newer treatments.42 43 Our Author affiliations 1 results suggested that HY≥10 has comparable effectiveness to Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, ≥ ≥ Taichung, Taiwan mBQT-14 and CT 10. The estimated effects of HY 10 rose 2Nuffield Department of Population Health, University of Oxford, Oxford, UK significantly to become the optimal regimen when to compare 3Blatvatnik School of Government, University of Oxford, Oxford, UK with TT-C-7 in the low clarithromycin resistant group. 4School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan 5Center for Health Policy Research and Development, Miaoli, Taiwan However, the results should be interpreted cautiously as there 6 were only three trials that studied HY≥10 in this subgroup. National Cancer Institute, National Health Research Institutes, Miaoli, Taiwan 7Department of Internal Medicine, National Taiwan University Hospital, Taipei, The effectiveness of BQT and quinolone-based TT are also Taiwan examined in the present study. Quinolone-based TT and BQT 8Faculty of Medicine and Institute of Clinical Medicine, National Yang-Ming are effective as a second-line or third-line rescue therapy, as University, Taipei, Taiwan 9 recommended in Maastricht Guidelines IV and the Toronto Department of Public Health and Graduate Institute of Clinical Medical Science, 413 fi China Medical University, Taichung, Taiwan Consensus. Our ndings supported the guidelines that 10Department of Life Sciences and Rong Hsing Research Center for Translational TT-Q≥10 and BQTs were superior to clarithromycin-based TT. Medicine, National Chung-Hsing University, Taichung, Taiwan In a recent meta-analysis that compared TT and BQT, Venerito et al indicated a non-significant difference between TT and BQT Acknowledgements We would like to thank all of the members of the Taiwan given in 7-day or 10-day to 14-day regimens.44 This observation Gastrointestinal Disease and Helicobacter Consortium (the member list is provided in fl fi ≥ the online supplementary appendix) for their valuable discussion of this manuscript. con icted with our ndings, as we showed that CT 10 was We would also like to thank Professor Yu-Kang, Tu from National Taiwan University superior to TT-C-14 and that CT≥7 was superior to TT-C-7. and Dr Anna Chaimani from University of Ioannina for their comments and However, this could be explained by the publication year of suggestions.

26 Yeo YH, et al. Gut 2017;67:20–27. doi:10.1136/gutjnl-2016-311868 Helicobacter pylori

Collaborators Consortium members are listed in the online supplementary 23 McNicholl AG NO, Gisbert JP. Sequential and concomitant treatments in H. pylori appendix. eradication: a network meta-analysis. Gastroenterology 2014;146:S-395. Gut: first published as 10.1136/gutjnl-2016-311868 on 26 September 2016. Downloaded from 24 Yuan Y, Ford AC, Khan KJ, et al. Optimum duration of regimens for Helicobacter Contributors C-YW, YHY, J-TL and M-SW designed the meta-analysis, with the pylori eradication. Cochrane Database Syst Rev 2013;(12):CD008337. inputs of all listed authors. YHY, S-IS and BZ contributed to data acquisition and 25 Calvet X, García N, López T, et al. A meta-analysis of short versus long therapy drafted the article. YHY, S-IS and HJH contributed to data analysis and with a proton pump inhibitor, clarithromycin and either metronidazole or interpretation. All authors performed critical revision of the manuscript and approved amoxycillin for treating Helicobacter pylori infection. Aliment Pharmacol Ther the final draft of the article. 2000;14:603–9. Funding This work was supported in part by the National Health Research 26 Ford A, Moayyedi P. How can the current strategies for Helicobacter pylori Institutes (PH-104-PP-23), Ministry of Science and Technology, Executive Yuan, ROC, eradication therapy be improved? Can J Gastroenterol 2003;17(Suppl B):36B–40B. Taiwan (MOST-103-2314-B-030-004-MY2) and Taichung Veterans General Hospital 27 Fuccio L, Minardi ME, Zagari RM, et al. Meta-analysis: duration of first-line (TCVGH-1043303C), Taiwan. proton-pump inhibitor based triple therapy for Helicobacter pylori eradication. Ann – Competing interests None declared. Intern Med 2007;147:553 62. 28 Zullo A, Rinaldi V, Winn S, et al. 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