PMID- 27351542
OWN - NLM
STAT- MEDLINE
DCOM- 20160817
LR  - 20220408
IS  - 1469-493X (Electronic)
IS  - 1361-6137 (Linking)
VI  - 2016
IP  - 6
DP  - 2016 Jun 28
TI  - Sequential versus standard triple first-line therapy for Helicobacter pylori 
      eradication.
PG  - CD009034
LID - 10.1002/14651858.CD009034.pub2 [doi]
LID - CD009034
AB  - 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 naive 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 
      (I(2) = 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; I(2) = 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; I(2) = 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).
FAU - Nyssen, Olga P
AU  - Nyssen OP
AD  - Gastroenterology Unit, Hospital Universitario de la Princesa, Instituto de 
      Investigacion Sanitaria Princesa (IIS-IP), and Centro de Investigacion Biomedica 
      en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Madrid, Madrid, Spain, 
      28006.
FAU - McNicholl, Adrian G
AU  - McNicholl AG
FAU - Megraud, Francis
AU  - Megraud F
FAU - Savarino, Vincenzo
AU  - Savarino V
FAU - Oderda, Giuseppina
AU  - Oderda G
FAU - Fallone, Carlo A
AU  - Fallone CA
FAU - Fischbach, Lori
AU  - Fischbach L
FAU - Bazzoli, Franco
AU  - Bazzoli F
FAU - Gisbert, Javier P
AU  - Gisbert JP
LA  - eng
PT  - Journal Article
PT  - Meta-Analysis
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PT  - Systematic Review
DEP - 20160628
PL  - England
TA  - Cochrane Database Syst Rev
JT  - The Cochrane database of systematic reviews
JID - 100909747
SB  - IM
UOF - doi: 10.1002/14651858.CD009034
MH  - Adult
MH  - Drug Therapy, Combination/methods
MH  - Geography, Medical
MH  - Helicobacter Infections/*drug therapy
MH  - *Helicobacter pylori
MH  - Humans
MH  - Intention to Treat Analysis
MH  - Randomized Controlled Trials as Topic
PMC - PMC8406793
COIS- Centro de Investigacion Biomedica en Red en el Area tematica de Enfermedades 
      Hepaticas 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 Megraud'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.
EDAT- 2016/06/29 06:00
MHDA- 2016/08/18 06:00
PMCR- 2017/06/28
CRDT- 2016/06/29 06:00
PHST- 2016/06/29 06:00 [entrez]
PHST- 2016/06/29 06:00 [pubmed]
PHST- 2016/08/18 06:00 [medline]
PHST- 2017/06/28 00:00 [pmc-release]
AID - CD009034.pub2 [pii]
AID - 10.1002/14651858.CD009034.pub2 [doi]
PST - epublish
SO  - Cochrane Database Syst Rev. 2016 Jun 28;2016(6):CD009034. doi: 
      10.1002/14651858.CD009034.pub2.