Cochrane Clinical Answers - Fulltext - How does sequential therapy compare with standard triple first-line therapy for the eradication of Helicobacter pylori?

Question:How does sequential therapy compare with standard triple first-line therapy for the eradication of Helicobacter pylori?

Clinical Answer:

Although sequential therapy appears to improve the Helicobacter pylori eradication rate compared with standard triple therapy, with no evidence of an increase in adverse events, effectiveness seems to differ across geographical regions and with different antibiotic resistance.

Moderate-quality evidence showed that sequential therapy increased the number of people in whom H. pylori was eradicated compared with standard triple therapy (from 751 per 1000 people to 833 per 1000). When subgroup analyses were conducted in people with antibiotic resistance, H. pylori eradication was greater with sequential therapy in people with any antibiotic resistance, or specifically with clarithromycin resistance.

Most of the trials used proton pump inhibitors (PPIs) with standard acid inhibition, therefore the result is most reflective of this type of PPI. Subgroup analyses showed no apparent impact of age, reason for therapy (non-ulcer or peptic ulcer disease) or type of nitroimidazole (metronidazole or tinidazole). However, the improvement in H. pylori eradication with sequential therapy was greater in trials conducted before 2008.

When trials were analyzed according to geographic region (Europe, Asia, Africa, South America), those conducted in Europe showed the greatest improvement, followed by Africa, then Asia. In South America, sequential therapy seemed to have a lower eradication rate than standard triple therapy. The quality of the evidence for these analyses was low.

High-quality evidence showed no difference in the incidence of adverse events between sequential therapy (2% to 57%) and standard triple therapy (2% to 55%). Review authors reported that interruption of treatment due to adverse events was approximately 1% with sequential therapy compared with 1.5% with standard triple therapy; the number of trials reporting this was unclear. Compliance was stated as being comparable between the two therapies across the 21 trials that reported this outcome. Compliance was defined variably across the trials, although most classified taking 90% and 95% of pills as good compliance.

Full outcome data is detailed below:

1.Sequential therapy versus standard triple first-line therapy

  • Population, Intervention, Comparator

    Population:

    Children and adults with confirmed Helicobacter pylori infection; there had to be at least one confirmatory test (monoclonal stool antigen test, rapid urease test, histology or culture of an endoscopic biopsy sample, or by urea breath test). Participants had to be H. pylori treatment-naïve. Twelve trials reported specifically on participants who had peptic ulcer-disease and/or non-ulcer disease. Studies were conducted in Italy (11 trials), Korea (8 trials), China (8 trials), India (2 trials), Morocco (2 trials) and one each in Iran, Spain, Latin-America, Poland, Puerto-Rico, Belgium, Slovenia, Kenya, Saudi Arabia, Brazil, Japan, Turkey and Singapore

    Intervention:

    Sequential therapy: Non-bismuth quadruple 10-day sequential therapy including a first induction phase with a dual regimen of amoxicillin (most commonly 1 g amoxicillin twice daily) and a proton pump inhibitor (PPI) for five days followed by a triple regimen phase with a PPI, clarithromycin (most commonly 500 mg) and nitroimidazole (metronidazole or tinidazole) for another five days

    Comparator:

    Standard triple first-line therapy (STT): 7 to 14-day therapy containing a PPI (regimens varied in type and dose: omeprazole, lansoprazole, pantoprazole, rabeprazole, or esomeprazole), antibiotics (most commonly 1 g amoxicillin twice daily; two trials used 30 to 40 mg/kg/day, one used 500 mg twice a day, one did not report the dose) and clarithromycin (most commonly 500 mg; two trials used 15 to 20 mg/kg/day and one did not report dose)

  • OUTCOME 1.1: Eradication/cure

    Quality of the evidence:

    The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was moderate quality. See Summary of findings from Cochrane review

    Narrative result:

    44 RCTs with 12,701 participants found that more people had H. pylori eradicated with sequential therapy compared with standard triple therapy. Subgroup analyses were conducted by level of acid inhibition (low, standard, high); most trials (36 trials, 9794 participants) used PPIs with standard acid inhibition, therefore the result of the main analysis reflected this subgroup.

    When children and adults or trials using metronidazole or tinidazole were analyzed separately, results were similar to the main analysis. Results for the different durations of STT (7, 10 or 14 days) were also similar to the main analysis, although the 14-day regimen did not quite reach statistical significance. When subgroup analyses were conducted based on medical condition (peptic ulcer disease, non-ulcer disease) results were similar to the main analysis, although neither analysis quite reached statistical significance.

    When subgroup analyses were conducted by geographic region, results for Europe, Asia, Africa were similar to the main analysis; fewer people had H. pylori eradicated with sequential therapy in South America. Results also varied across subgroups that assessed H. pylori eradication in people with antibiotic resistant strains. More people had H. pylori eradicated with sequential therapy with any antibiotic resistance or clarithromycin resistance.

    Although more people had H. pylori eradicated with sequential therapy compared with standard triple therapy in trials published before and after 2008, the difference was greater in trials published before 2008. Click below for full details.

    Relative effect or mean difference:

    There was a statistically significant difference between groups, in favor of sequential therapy (risk difference 9%, 95% CI 6% to 11%).

    Forest plot from Cochrane Review

    Absolute effect:

    833 per 1000 people (95% CI 811 to 863) with sequential therapy compared with 751 per 1000 people with standard triple therapy.

    Reference:
    Nyssen OP, McNicholl AG, Megraud F, Savarino V, Oderda G, Fallone CA, Fischbach L, Bazzoli F, Gisbert JP. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD009034. DOI: 10.1002/14651858.CD009034.pub2. [Review search date: April 2015]
    • Subgroup analysis 1.1.1: Eradication/cure - [subgroup: Geographic region Europe]
      Quality of the evidence:

      The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was low quality. See Summary of findings from Cochrane review

      Narrative result:

      15 RCTs with 3796 participants found that sequential therapy increased eradication rates in Europe compared with standard therapy.

      Relative effect or mean difference:

      There was a statistically significant difference between groups, in favor of sequential therapy (risk difference 16%, 95% CI 14% to 19%).

      Forest plot from Cochrane Review

      Reference:
      Nyssen OP, McNicholl AG, Megraud F, Savarino V, Oderda G, Fallone CA, Fischbach L, Bazzoli F, Gisbert JP. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD009034. DOI: 10.1002/14651858.CD009034.pub2. [Review search date: April 2015]
    • Subgroup analysis 1.1.2: Eradication/cure - [subgroup: Geographic region Asia]
      Quality of the evidence:

      The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was low quality. See Summary of findings from Cochrane review

      Narrative result:

      23 RCTs with 6728 participants found that sequential therapy increased eradication rates in Asia compared with standard therapy.

      Relative effect or mean difference:

      There was a statistically significant difference between groups, in favor of sequential therapy (risk difference 5%, 95% CI 2% to 8%).

      Forest plot from Cochrane Review

      Reference:
      Nyssen OP, McNicholl AG, Megraud F, Savarino V, Oderda G, Fallone CA, Fischbach L, Bazzoli F, Gisbert JP. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD009034. DOI: 10.1002/14651858.CD009034.pub2. [Review search date: April 2015]
    • Subgroup analysis 1.1.3: Eradication/cure - [subgroup: Geographic region Africa]
      Quality of the evidence:

      The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was low quality. See Summary of findings from Cochrane review

      Narrative result:

      Three RCTs with 604 participants found that sequential therapy increased eradication rates in Africa compared with standard therapy.

      Relative effect or mean difference:

      There was a statistically significant difference between groups, in favor of sequential therapy (risk difference 14%, 95% CI 7% to 22%).

      Forest plot from Cochrane Review

      Reference:
      Nyssen OP, McNicholl AG, Megraud F, Savarino V, Oderda G, Fallone CA, Fischbach L, Bazzoli F, Gisbert JP. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD009034. DOI: 10.1002/14651858.CD009034.pub2. [Review search date: April 2015]
    • Subgroup analysis 1.1.4: Eradication/cure - [subgroup: Geographic region South America]
      Quality of the evidence:

      The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was low quality. See Summary of findings from Cochrane review

      Narrative result:

      Three RCTs with 1156 participants found that fewer people in South America had H. pylori eradicated with sequential therapy compared with standard triple therapy.

      Relative effect or mean difference:

      There was a statistically significant difference between groups, in favor of standard triple therapy (RD -6%, 95% CI -10% to -1%).

      Forest plot from Cochrane Review

      Reference:
      Nyssen OP, McNicholl AG, Megraud F, Savarino V, Oderda G, Fallone CA, Fischbach L, Bazzoli F, Gisbert JP. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD009034. DOI: 10.1002/14651858.CD009034.pub2. [Review search date: April 2015]
    • Subgroup analysis 1.1.5: Eradication/cure - [subgroup: Clarithromycin resistance]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. Of the eight studies, two (25%) failed to report adequate allocation concealment or random sequence generation, six (75%) did not report blinding of participants/carers/outcome assessors and two (25%) had high or unclear numbers of withdrawals.

      Narrative result:

      Eight RCTs with 214 participants found that more people with clarithromycin resistance had H. pylori eradicated with sequential therapy compared with standard triple therapy.

      Relative effect or mean difference:

      There was a statistically significant difference between groups, in favor of sequential therapy (risk difference 33%, 95% CI 13% to 54%).

      Forest plot from Cochrane Review

      Reference:
      Nyssen OP, McNicholl AG, Megraud F, Savarino V, Oderda G, Fallone CA, Fischbach L, Bazzoli F, Gisbert JP. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD009034. DOI: 10.1002/14651858.CD009034.pub2. [Review search date: April 2015]
    • Subgroup analysis 1.1.6: Eradication/cure - [subgroup: Nitroimidazole resistance]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. Of the seven studies, one (14%) did not use adequate allocation concealment or random sequence generation, five (71%) did not report blinding of participants/carers/outcome assessors and two (28%) had high or unclear numbers of withdrawals.

      Narrative result:

      Seven RCTs with 413 participants found no statistically significant difference between groups.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (risk difference 4%, 95% CI -6% to 14%).

      Forest plot from Cochrane Review

      Reference:
      Nyssen OP, McNicholl AG, Megraud F, Savarino V, Oderda G, Fallone CA, Fischbach L, Bazzoli F, Gisbert JP. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD009034. DOI: 10.1002/14651858.CD009034.pub2. [Review search date: April 2015]
    • Subgroup analysis 1.1.7: Eradication/cure - [subgroup: Dual resistance]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. Of the six studies, one (17%) did not use adequate allocation concealment or random sequence generation, four (67%) did not report blinding of participants/carers/outcome assessors and one (17%) had high or unclear numbers of withdrawals.

      Narrative result:

      Six RCTs with 205 participants found no statistically significant difference between groups.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (risk difference 3%, 95% CI -14% to 19%).

      Forest plot from Cochrane Review

      Reference:
      Nyssen OP, McNicholl AG, Megraud F, Savarino V, Oderda G, Fallone CA, Fischbach L, Bazzoli F, Gisbert JP. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD009034. DOI: 10.1002/14651858.CD009034.pub2. [Review search date: April 2015]
    • Subgroup analysis 1.1.8: Eradication/cure - [subgroup: Publication date before 2008]
      Quality of the evidence:

      The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was moderate quality. See Summary of findings from Cochrane review

      Narrative result:

      Eight RCTs with 2730 participants found that more people had H. pylori eradicated with sequential therapy compared with standard triple therapy in trials published before 2008.

      Relative effect or mean difference:

      There was a statistically significant difference between groups, in favor of sequential therapy (risk difference 16%, 95% CI 14% to 19%).

      Forest plot from Cochrane Review

      Reference:
      Nyssen OP, McNicholl AG, Megraud F, Savarino V, Oderda G, Fallone CA, Fischbach L, Bazzoli F, Gisbert JP. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD009034. DOI: 10.1002/14651858.CD009034.pub2. [Review search date: April 2015]
    • Subgroup analysis 1.1.9: Eradication/cure - [subgroup: Publication date after 2008]
      Quality of the evidence:

      The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was moderate quality. See Summary of findings from Cochrane review

      Narrative result:

      36 RCTs with 10021 participants found that more people had H. pylori eradicated with sequential therapy compared with standard triple therapy in trials published after 2008.

      Relative effect or mean difference:

      There was a statistically significant difference between groups, in favor of sequential therapy (risk difference 6%, 95% CI 3% to 9%).

      Forest plot from Cochrane Review

      Reference:
      Nyssen OP, McNicholl AG, Megraud F, Savarino V, Oderda G, Fallone CA, Fischbach L, Bazzoli F, Gisbert JP. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD009034. DOI: 10.1002/14651858.CD009034.pub2. [Review search date: April 2015]
  • OUTCOME 1.2: Adverse events

    Quality of the evidence:

    The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was high quality. See Summary of findings from Cochrane review

    Narrative result:

    27 RCTs with 8103 participants found no statistically significant difference between groups. The incidence of adverse events ranged from 2% to 57% with sequential therapy compared with 2% to 55% with standard triple therapy. Common adverse events were abdominal pain, diarrhea, nausea, glossitis and vomiting.

    Relative effect or mean difference:

    There was no statistically significant difference between groups (risk difference 0%, 95% CI -1% to 2%).

    Forest plot from Cochrane Review

    Absolute effect:

    199 per 1000 people (95% CI 176 to 215) with sequential therapy compared with 195 per 1000 people with standard triple therapy.

    Reference:
    Nyssen OP, McNicholl AG, Megraud F, Savarino V, Oderda G, Fallone CA, Fischbach L, Bazzoli F, Gisbert JP. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD009034. DOI: 10.1002/14651858.CD009034.pub2. [Review search date: April 2015]
    • OUTCOME 1.3: Withdrawals due to adverse events

      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The trials contributing to this outcome were unclear, therefore the potential risk of bias cannot be assessed.

      Narrative result:

      The review stated that the interruption of treatment due to adverse events was similar across groups: approx. 1% with sequential therapy compared with 1.5% with standard triple therapy. The number of trials reporting this outcome was unclear.

      Relative effect or mean difference:

      Results were reported narratively.

      Reference:
      Nyssen OP, McNicholl AG, Megraud F, Savarino V, Oderda G, Fallone CA, Fischbach L, Bazzoli F, Gisbert JP. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD009034. DOI: 10.1002/14651858.CD009034.pub2. [Review search date: April 2015]
      • OUTCOME 1.4: Compliance/adherence

        Risk of bias of studies:

        The reviewers did not perform a GRADE assessment of the quality of the evidence. The trials contributing to this outcome were unclear, therefore the potential risk of bias cannot be assessed.

        Narrative result:

        21 RCTs with an unclear number of participants reported that compliance was comparable across groups (data not provided). Compliance was defined variably across the trials. Most classified taking 90% and 95% of pills as good compliance.

        Relative effect or mean difference:

        Results were reported narratively.

        Reference:
        Nyssen OP, McNicholl AG, Megraud F, Savarino V, Oderda G, Fallone CA, Fischbach L, Bazzoli F, Gisbert JP. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD009034. DOI: 10.1002/14651858.CD009034.pub2. [Review search date: April 2015]
        • OUTCOME 1.5: Adverse events (serious, gastrointestinal, systemic)

          Narrative result:

          The review reported no trials that assessed these outcomes.

          Reference:
          Nyssen OP, McNicholl AG, Megraud F, Savarino V, Oderda G, Fallone CA, Fischbach L, Bazzoli F, Gisbert JP. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD009034. DOI: 10.1002/14651858.CD009034.pub2. [Review search date: April 2015]

          Additional Information:

          DOI

          10.1002/cca.1532

          Publication Dates

          1. Published Online: 2 MAR 2017

          CCA derived from

          Nyssen OP, McNicholl AG, Megraud F, Savarino V, Oderda G, Fallone CA, Fischbach L, Bazzoli F, Gisbert JP. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD009034. DOI: 10.1002/14651858.CD009034.pub2. [Review search date: April 2015]

          How to Cite

          How does sequential therapy compare with standard triple first-line therapy for the eradication of Helicobacter pylori? Kurinchi Gurusamy (MBBS, MRCS, PhD) (on behalf of Cochrane Clinical Answers Editors). Cochrane Clinical Answers 2017. DOI: 10.1002/cca.1532.

          Further Information

          • CCA Associate editor: Kurinchi Gurusamy (MBBS, MRCS, PhD), Lecturer in Surgery, University College London, London, UK.
          • CCA Editor: Karen Pettersen. Correspondence to kpettersen@wiley.com.