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Review
. 2016 Jun 28;2016(6):CD009034.
doi: 10.1002/14651858.CD009034.pub2.

Sequential versus standard triple first-line therapy for Helicobacter pylori eradication

Olga P Nyssen  1 , Adrian G McNicholl, Francis Megraud, Vincenzo Savarino, Giuseppina Oderda, Carlo A Fallone, Lori Fischbach, Franco Bazzoli, Javier P Gisbert
Affiliations
Review

Sequential versus standard triple first-line therapy for Helicobacter pylori eradication

Olga P Nyssen et al. Cochrane Database Syst Rev. .

Abstract

Background: Non-bismuth quadruple sequential therapy (SEQ) comprising a first induction phase with a dual regimen of amoxicillin and a proton pump inhibitor (PPI) for five days followed by a triple regimen phase with a PPI, clarithromycin and metronidazole for another five days, has been suggested as a new first-line treatment option to replace the standard triple therapy (STT) comprising a proton pump inhibitor (PPI), clarithromycin and amoxicillin, in which eradication proportions have declined to disappointing levels.

Objectives: To conduct a meta-analysis of randomised controlled trials (RCTs) comparing the efficacy of a SEQ regimen with STT for the eradication of H. pylori infection, and to compare the incidence of adverse effects associated with both STT and SEQ H. pylori eradication therapies.

Search methods: We conducted bibliographical searches in electronic databases, and handsearched abstracts from Congresses up to April 2015.

Selection criteria: We sought randomised controlled trials (RCTs) comparing 10-day SEQ and STT (of at least seven days) for the eradication of H. pylori. Participants were adults and children diagnosed as positive for H. pylori infection and naïve to H. pylori treatment.

Data collection and analysis: We used a pre-piloted, tabular summary to collect demographic and medical information of included study participants as well as therapeutic data and information related to the diagnosis and confirmatory tests.We evaluated the difference in intention-to-treat eradication between SEQ and STT regimens across studies, and assessed sources of the heterogeneity of this risk difference (RD) using subgroup analyses.We evaluated the quality of the evidence following Cochrane standards, and summarised it using GRADE methodology.

Main results: We included 44 RCTs with a total of 12,284 participants (6042 in SEQ and 6242 in STT). The overall analysis showed that SEQ was significantly more effective than STT (82% vs 75% in the intention-to-treat analysis; RD 0.09, 95% confidence interval (CI) 0.06 to 0.11; P < 0.001, moderate-quality evidence). Results were highly heterogeneous (I² = 75%), and 20 studies did not demonstrate differences between therapies.Reporting by geographic region (RD 0.09, 95% CI 0.06 to 0.12; studies = 44; I² = 75%, based on low-quality evidence) showed that differences between SEQ and STT were greater in Europe (RD 0.16, 95% CI 0.14 to 0.19) when compared to Asia, Africa or South America. European studies also showed a tendency towards better efficacy with SEQ; however, this tendency was reversed in 33% of the Asian studies. Africa reported the closest risk difference (RD 0.14 , 95% 0.07 to 0.22) to Europe among studied regions, but confidence intervals were wider and therefore the quality of the evidence showing SEQ to be superior to STT was reduced for this region.Based on high-quality evidence, subgroup analyses showed that SEQ and STT therapies were equivalent when STT lasted for 14 days. Although, overall, the mean eradication proportion with SEQ was over 80%, we noted a tendency towards a lower average effect with this regimen in the more recent studies (2008 and after); weighted linear regression showed that the efficacies of both regimens evolved differently over the years, having a higher reduction in the efficacy of SEQ (-1.72% yearly) than in STT (-0.9% yearly). In these more recent studies (2008 and after) we were also unable to detect the superiority of SEQ over STT when STT was given for 10 days.Based on very low-quality evidence, subgroup analyses on antibiotic resistance showed that the widest difference in efficacy between SEQ and STT was in the subgroup analysis based on clarithromycin-resistant participants, in which SEQ reached a 75% average efficacy versus 43% with STT.Reporting on adverse events (AEs) (RD 0.00, 95% CI -0.02 to 0.02; participants = 8103; studies = 27; I² = 26%, based on high-quality evidence) showed no significant differences between SEQ and STT (20.4% vs 19.5%, respectively) and results were homogeneous.The quality of the studies was limited due to a lack of systematic reporting of the factors affecting risk of bias. Although randomisation was reported, its methodology (e.g. algorithms, number of blocks) was not specified in several studies. Additionally, the other 'Risk of bias' domains (such as allocation concealment of the sequence randomisation, or blinding during either performance or outcome assessment) were also unreported.However, subgroup analyses as well as sensitivity analyses or funnel plots indicated that treatment outcomes were not influenced by the quality of the included studies. On the other hand, we rated 'length of STT' and AEs for the main outcome as high-quality according to GRADE classification; but we downgraded 'publication date' quality to moderate, and 'geographic region' and 'antibiotic resistance' to low- and very low-quality, respectively.

Authors' conclusions: Our meta-analysis indicates that prior to 2008 SEQ was more effective than STT, especially when STT was given for only seven days. Nevertheless, the apparent advantage of sequential treatment has decreased over time, and more recent studies do not show SEQ to have a higher efficacy versus STT when STT is given for 10 days.Based on the results of this meta-analysis, although SEQ offers an advantage when compared with STT, it cannot be presented as a valid alternative, given that neither SEQ nor STT regimens achieved optimal efficacy ( ≥ 90% eradication rate).

PubMed Disclaimer

Conflict of interest statement

Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd) is funded by Instituto de Salud Carlos III.

OPN: none known.

AGMcN: Dr McNicholl received fees from Allergan form speaking in 2016.

FM: Dr Mégraud's Institution received grants from Aphtalis Pharma.

VS: Prof. Vincenzo Savarino has received honoraria for speaker in medical congresses and consulting work from; Takeda Italia, Alfa Wassermann, Almirall, MSD, Abbvie, Reckitt Benckiser and Pfizer. All honoraria were received more than three years ago.

GO: none known.

CAF: Dr Fallone has done consulting work in the past three years for Pendopharm, Canada, Takeda, Canada, Janssen, Canada, Forest Laboratories, Canada and Actavis, Canada.

LF: Dr Fischbach was paid by Axcan Pharma to participate in an educational programme on treatment for H. pylori more than five years ago.

FB: Dr Bazzoli has received fees from Allergan for consulting work done in the past three years.

JPG: Dr. Gisbert has served as a speaker, a consultant and advisory member for, or has received research funding from, MSD, Abbvie, Hospira, Kern Pharma, Biogen, Takeda, Janssen, Pfizer, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Vifor Pharma, Almirall, Nycomed, AstraZeneca, Casen Recordati, Allergan. Dr Gisbert is an editor with the Cochrane Upper GI and Pancreatic Diseases group. Dr Gisbert was not involved in the editorial processing of this review.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Weighted linear regression line in SEQ and STT by year of publication
5
5
Radar chart depicting the eradication proportion for SEQ and STT in each included study
6
6
Forest plot of comparison: 1 Sequential therapy versus standard triple therapy, outcome: 1.3 Publication date.
See this image and copyright information in PMC

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References

References to studies included in this review

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Molina‐Infante 2010 {published data only}
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Paoluzi 2010 {published data only}
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Rakici 2014 {published data only}
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Scaccianoce 2006 {published data only}
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Vaira 2007 {published data only}
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References to studies excluded from this review

Francavilla 2005 {published data only}
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References to other published versions of this review

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