Optimum duration of regimens for Helicobacter pylori eradication.

Cochrane Database of Systematic Reviews

Optimum duration of regimens for Helicobacter pylori eradication (Review) Yuan Y, Ford AC, Khan KJ, Gisbert JP, Forman D, Leontiadis GI, Tse F, Calvet X, Fallone C, Fischbach L, Oderda G, Bazzoli F, Moayyedi P

Yuan Y, Ford AC, Khan KJ, Gisbert JP, Forman D, Leontiadis GI, Tse F, Calvet X, Fallone C, Fischbach L, Oderda G, Bazzoli F, Moayyedi P. Optimum duration of regimens for #Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD008337. DOI: 10.1002/14651858.CD008337.pub2.

www.cochranelibrary.com

Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS

HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 PPI + two antibiotics triple therapy, 14 days versus 7 days, main analyses, Outcome 1 H. pylori persistence, subgroup by antibiotics regimens, regardless of dose. . . . . . . . . . . . . . . . . Analysis 1.2. Comparison 1 PPI + two antibiotics triple therapy, 14 days versus 7 days, main analyses, Outcome 2 Patients with adverse events, subgroup by antibiotics regimens, regardless of dose. . . . . . . . . . . . . . Analysis 1.3. Comparison 1 PPI + two antibiotics triple therapy, 14 days versus 7 days, main analyses, Outcome 3 Patients discontinued treatment due to adverse events, subgroup by antibiotics regimens, regardless of dose. . . . . Analysis 2.1. Comparison 2 PPI + two antibiotics triple therapy, 10 days versus 7 days, main analyses, Outcome 1 H. pylori persistence, subgroup by antibiotics regimens, regardless of dose. . . . . . . . . . . . . . . . . Analysis 2.2. Comparison 2 PPI + two antibiotics triple therapy, 10 days versus 7 days, main analyses, Outcome 2 Patients with adverse events, subgroup by antibiotics regimen, regardless of dose. . . . . . . . . . . . . . . Analysis 2.3. Comparison 2 PPI + two antibiotics triple therapy, 10 days versus 7 days, main analyses, Outcome 3 Patients discontinued treatment due to adverse events, subgroup by antibiotics regimen, regardless of dose. . . . . . Analysis 3.1. Comparison 3 PPI + two antibiotics triple therapy, 14 days versus 10 days, main analyses, Outcome 1 H. pylori persistence, subgroup by antibiotics regimen, regardless of dose. . . . . . . . . . . . . . . Analysis 3.2. Comparison 3 PPI + two antibiotics triple therapy, 14 days versus 10 days, main analyses, Outcome 2 Patients with adverse events, subgroup by antibiotics, regardless of dose. . . . . . . . . . . . . . . . . . Analysis 3.3. Comparison 3 PPI + two antibiotics triple therapy, 14 days versus 10 days, main analyses, Outcome 3 Patients discontinued treatment due to adverse events, subgroup by antibiotics regimens, regardless of dose. . . . . Analysis 4.1. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimens. . . . . . . . . . . . . . . . . Analysis 4.2. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 2 H. pylori persistence, subgroup by location. . . . . . . . . . . . . . . . . Analysis 4.3. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 3 H. pylori persistence, subgroup by baseline PUD or FD. . . . . . . . . . . . Analysis 4.4. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 4 H. pylori persistence, subgroup by risk of bias: allocation concealment. . . . . . . Analysis 4.5. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 5 H. pylori persistence, subgroup by risk of bias: overall. . . . . . . . . . . . . Analysis 4.6. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 6 Patients with adverse events. . . . . . . . . . . . . . . . . . . . . . Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Analysis 4.7. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 7 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . Analysis 4.8. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 8 Adverse events: Diarrhoea/ loose stool/increasing stool passage. . . . . . . . . . Analysis 4.9. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 9 Adverse event: Taste disturbance/metallic taste or glossitis. . . . . . . . . . . . Analysis 4.10. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 10 Adverse event: Nausea or vomiting. . . . . . . . . . . . . . . . . . . Analysis 4.11. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 11 Adverse events: Skin rash and/or itching/allergic cutaneous reactions. . . . . . . . Analysis 4.12. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 12 Adverse event: Epigastric discomfort / Abdominal pain. . . . . . . . . . . . Analysis 4.13. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 13 Adverse event: Headache. . . . . . . . . . . . . . . . . . . . . . . Analysis 4.14. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 14 Adverse event: Dry mouth/throat or thirsty. . . . . . . . . . . . . . . . Analysis 4.15. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 15 Adverse event: Stomatitis/Angular stomatitis. . . . . . . . . . . . . . . . Analysis 4.16. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 16 Adverse event: Loss of appetite. . . . . . . . . . . . . . . . . . . . . Analysis 4.17. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 17 Adverse event: Tongue discolouration. . . . . . . . . . . . . . . . . . Analysis 4.18. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 18 Adverse event: Dizziness. . . . . . . . . . . . . . . . . . . . . . . Analysis 4.19. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 19 Adverse event: Regurgitation/belching. . . . . . . . . . . . . . . . . . Analysis 4.20. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 20 Adverse event: Bloating. . . . . . . . . . . . . . . . . . . . . . . Analysis 4.21. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 21 Adverse event: Discolored faeces. . . . . . . . . . . . . . . . . . . . Analysis 4.22. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 22 Adverse event: Monilia. . . . . . . . . . . . . . . . . . . . . . . Analysis 4.23. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 23 Adverse event: Herpes simplex labialis. . . . . . . . . . . . . . . . . . Analysis 5.1. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimen. . . . . . . . . . . . . . . . . Analysis 5.2. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 2 H. pylori persistence, subgroup by location. . . . . . . . . . . . . . . . . Analysis 5.3. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 3 H. pylori persistence, subgroup by baseline PUD or FD. . . . . . . . . . . . Analysis 5.4. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 4 H. pylori persistence, subgroup by risk of bias: allocation concealment. . . . . . . Analysis 5.5. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 5 H. pylori persistence, subgroup by risk of bias: overall. . . . . . . . . . . . . Analysis 5.6. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 6 Patients with adverse events. . . . . . . . . . . . . . . . . . . . . . Analysis 5.7. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 7 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . Analysis 5.8. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 8 Adverse events: Taste disturbance or glossitis. . . . . . . . . . . . . . . . Analysis 5.9. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 9 Adverse event: Diarrhoea. . . . . . . . . . . . . . . . . . . . . . . Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Analysis 5.10. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 10 Adverse event: Nausea or Vomiting. . . . . . . . . . . . . . . . . . . Analysis 5.11. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 11 Adverse event: Abdominal pain. . . . . . . . . . . . . . . . . . . . . Analysis 5.12. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 12 Adverse event: Skin rash or pruritus. . . . . . . . . . . . . . . . . . . Analysis 5.13. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 13 Adverse event: Headache. . . . . . . . . . . . . . . . . . . . . . . Analysis 5.14. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 14 Adverse event: Dyspepsia or worsened dyspepsia. . . . . . . . . . . . . . . Analysis 5.15. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 15 Adverse event: Flatulence. . . . . . . . . . . . . . . . . . . . . . . Analysis 5.16. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 16 Adverse event: Infection. . . . . . . . . . . . . . . . . . . . . . . Analysis 5.17. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 17 Adverse event: Anorexia. . . . . . . . . . . . . . . . . . . . . . . Analysis 5.18. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 18 Adverse event: Loss appetite. . . . . . . . . . . . . . . . . . . . . . Analysis 5.19. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 19 Adverse event: Erythaema. . . . . . . . . . . . . . . . . . . . . . Analysis 5.20. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 20 Adverse event: Candidiasis. . . . . . . . . . . . . . . . . . . . . . Analysis 5.21. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 21 Adverse event: Authors’ defined “serious adverse events”. . . . . . . . . . . . Analysis 6.1. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimen. . . . . . . . . . . . . . . . . Analysis 6.2. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 2 H. pylori persistence, subgroup by location. . . . . . . . . . . . . . . . . Analysis 6.3. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 3 H. pylori persistence, subgroup by baseline PUD or FD. . . . . . . . . . . . Analysis 6.4. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 4 H. pylori persistence, subgroup by risk of bias: allocation concealment. . . . . . . Analysis 6.5. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 5 H. pylori persistence, subgroup by risk of bias: overall. . . . . . . . . . . . . Analysis 6.6. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 6 Patients with adverse events. . . . . . . . . . . . . . . . . . . . . . Analysis 6.7. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 7 Patients discontinued treatment due to adverse events. . . . . . . . . . . . . Analysis 6.8. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 8 Adverse event: Nausea/Vomiting. . . . . . . . . . . . . . . . . . . . . Analysis 6.9. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 9 Adverse event: Diarrhoea. . . . . . . . . . . . . . . . . . . . . . . Analysis 6.10. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 10 Adverse event: Taste disturbance or glossitis. . . . . . . . . . . . . . . . Analysis 6.11. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 11 Adverse event: Headache. . . . . . . . . . . . . . . . . . . . . . . Analysis 6.12. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 12 Adverse event: Loss of appetite. . . . . . . . . . . . . . . . . . . . . Analysis 6.13. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 13 Adverse event: Abdominal pain. . . . . . . . . . . . . . . . . . . . . Analysis 6.14. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 14 Adverse event: Skin rash or itching. . . . . . . . . . . . . . . . . . . Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Analysis 7.1. Comparison 7 PPI + clarithromycin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimen. . . . . . . . . . . . . . . . . Analysis 7.2. Comparison 7 PPI + clarithromycin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 2 H. pyloris persistence, subgroup by location. . . . . . . . . . . . . . . . . Analysis 7.3. Comparison 7 PPI + clarithromycin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 3 H. pyloris persistence, subgroup by baseline PUD or FD. . . . . . . . . . . . Analysis 7.4. Comparison 7 PPI + clarithromycin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 4 H. pyloris persistence, subgroup by risk of bias: overall. . . . . . . . . . . . . Analysis 7.5. Comparison 7 PPI + clarithromycin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 5 Patients with adverse events. . . . . . . . . . . . . . . . . . . . . . Analysis 7.6. Comparison 7 PPI + clarithromycin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 6 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . Analysis 8.1. Comparison 8 PPI + clarithromycin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimen. . . . . . . . . . . . . . . . . Analysis 8.2. Comparison 8 PPI + clarithromycin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 2 Patients with adverse events. . . . . . . . . . . . . . . . . . . . . . Analysis 8.3. Comparison 8 PPI + clarithromycin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 3 Patients discontined treatment due to adverse events. . . . . . . . . . . . . . Analysis 9.1. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimen. . . . . . . . . . . . . . . . . Analysis 9.2. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 2 H. pylori persistence subgroup by location. . . . . . . . . . . . . . . . . Analysis 9.3. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 3 H. pylori persistence, subgroup by baseline PUD or FD. . . . . . . . . . . . Analysis 9.4. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 4 H. pylori persistence subgroup by risk of bias: allocation concealment. . . . . . . . Analysis 9.5. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 5 H. pylori persistence subgroup by risk of bias: overall. . . . . . . . . . . . . Analysis 9.6. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 6 Patients with adverse events. . . . . . . . . . . . . . . . . . . . . . Analysis 9.7. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 7 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . Analysis 9.8. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 8 Adverse events: Diarrhoea. . . . . . . . . . . . . . . . . . . . . . . Analysis 9.9. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 9 Adverse event: Nausea/vomiting/epigastric discomfort. . . . . . . . . . . . . Analysis 9.10. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 10 Adverse events: Metallic taste/dysgeusia/taste disturbance. . . . . . . . . . . . Analysis 9.11. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 11 Adverse event: Epigastric pain/abdominal pain. . . . . . . . . . . . . . . Analysis 9.12. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 12 Adverse event: Dizziness. . . . . . . . . . . . . . . . . . . . . . . Analysis 9.13. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 13 Adverse events: Skin rush. . . . . . . . . . . . . . . . . . . . . . . Analysis 9.14. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 14 Adverse event: Headache. . . . . . . . . . . . . . . . . . . . . . . Analysis 9.15. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 15 Adverse event: Flatulence. . . . . . . . . . . . . . . . . . . . . . . Analysis 9.16. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 16 Adverse event: Malaise. . . . . . . . . . . . . . . . . . . . . . . . Analysis 9.17. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 17 Adverse event: Heartburn. . . . . . . . . . . . . . . . . . . . . . . Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Analysis 9.18. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 18 Advere event: Regurgitation. . . . . . . . . . . . . . . . . . . . . . Analysis 9.19. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 19 Adverse event: Pruritus. . . . . . . . . . . . . . . . . . . . . . . Analysis 9.20. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 20 Adverse event: Loss of appetite. . . . . . . . . . . . . . . . . . . . . Analysis 10.1. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimen. . . . . . . . . . . . . . . . . Analysis 10.2. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 2 H. pylori persistence subgroup by location. . . . . . . . . . . . . . . . . Analysis 10.3. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 3 H. pylori persistence subgroup by baseline PUD or FD. . . . . . . . . . . . . Analysis 10.4. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 4 H. pylori persistence, subgroup by risk of bias: allocation concealment. . . . . . . Analysis 10.5. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 5 H. pylori persistence, subgroup by risk of bias: overall. . . . . . . . . . . . . Analysis 10.6. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 6 Patients with adverse events. . . . . . . . . . . . . . . . . . . . . . Analysis 10.7. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 7 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . Analysis 10.8. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 8 Adverse event: Nausea/Vomiting. . . . . . . . . . . . . . . . . . . . . Analysis 10.9. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 9 Adverse event: Diarrhoea. . . . . . . . . . . . . . . . . . . . . . . Analysis 10.10. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 10 Adverse event: Abdominal pain. . . . . . . . . . . . . . . . . . . Analysis 10.11. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 11 Adverse event: Loss of appetite. . . . . . . . . . . . . . . . . . . Analysis 10.12. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 12 Adverse event: Headache. . . . . . . . . . . . . . . . . . . . . Analysis 10.13. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 13 Adverse event: Taste disturbance. . . . . . . . . . . . . . . . . . . Analysis 11.1. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimen. . . . . . . . . . . . . . . . Analysis 11.2. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 2 H. pylori persistence subgroup by location. . . . . . . . . . . . . . . . Analysis 11.3. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 3 H. pylori persistence, subgroup by baseline PUD or FD. . . . . . . . . . . Analysis 11.4. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 4 H. pylori persistence, subgroup by risk of bias: allocation concealment. . . . . . Analysis 11.5. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 5 H. pylori persistence, subgroup by risk of bias: overall. . . . . . . . . . . . Analysis 11.6. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 6 Patients with adverse events. . . . . . . . . . . . . . . . . . . . . Analysis 11.7. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 7 Patients discontinuing treatment due to adverse event. . . . . . . . . . . . Analysis 11.8. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 8 Adverse event: Diarrhoea. . . . . . . . . . . . . . . . . . . . . . Analysis 11.9. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 9 Adverse event: Dysgeusia/taste disturbance. . . . . . . . . . . . . . . . Analysis 11.10. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 10 Adverse event: Nausea/Vomiting. . . . . . . . . . . . . . . . . . . Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

286 286 287 287 289 290 291 292 293 293 294 295 295 296 296 297 297 299 300 301 302 303 303 304 305 306 v

Analysis 11.11. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 11 Adverse event: Headache. . . . . . . . . . . . . . . . . . . . . Analysis 11.12. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 12 Adverse event: Loss of appetite. . . . . . . . . . . . . . . . . . . Analysis 11.13. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 13 Adverse event: Abdominal pain. . . . . . . . . . . . . . . . . . . Analysis 12.1. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimens. . . . . . . . . . . . . . . . . Analysis 12.2. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 2 H. pylori persistence: subgroup by location. . . . . . . . . . . . . . . . . Analysis 12.3. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 3 H. pylori persistence: subgroup by baseline PUD or FD. . . . . . . . . . . . Analysis 12.4. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 4 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . Analysis 12.5. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 5 Adverse events: Diarrhoea. . . . . . . . . . . . . . . . . . . . . . . Analysis 12.6. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 6 Adverse events: Headache. . . . . . . . . . . . . . . . . . . . . . . Analysis 12.7. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 7 Adverse events: Skin rush or pruritus. . . . . . . . . . . . . . . . . . . Analysis 12.8. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 8 Adverse event: nausea/vomiting. . . . . . . . . . . . . . . . . . . . . Analysis 12.9. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 9 Adverse event: Allergic reaction. . . . . . . . . . . . . . . . . . . . . Analysis 13.1. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimens. . . . . . . . . . . . . . . . . Analysis 13.2. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 2 H. pylori persistence subgroup by location. . . . . . . . . . . . . . . . . Analysis 13.3. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 3 H. pylori persistence subgroup by baseline PUD or FD. . . . . . . . . . . . . Analysis 13.4. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 4 Patients with adverse events. . . . . . . . . . . . . . . . . . . . . . Analysis 13.5. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 5 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . Analysis 13.6. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 6 Adverse event: Epigastric discomfort/abdominal pain. . . . . . . . . . . . . Analysis 13.7. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 7 Adverse event: Nausea or vomiting. . . . . . . . . . . . . . . . . . . . Analysis 13.8. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 8 Adverse event: Diarrrhoea. . . . . . . . . . . . . . . . . . . . . . . Analysis 13.9. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 9 Adverse event: Metallic taste/taste disturbances. . . . . . . . . . . . . . . . Analysis 13.10. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 10 Adverse event: Constipation. . . . . . . . . . . . . . . . . . . . . . Analysis 13.11. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 11 Adverse event: Headache. . . . . . . . . . . . . . . . . . . . . . . Analysis 13.12. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 12 Adverse event: Pruritus. . . . . . . . . . . . . . . . . . . . . . . Analysis 13.13. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 13 Adverse event: Skin rash. . . . . . . . . . . . . . . . . . . . . . . Analysis 13.14. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 14 Adverse event: Aphthous stomatitis. . . . . . . . . . . . . . . . . . . Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

307 307 308 308 309 310 311 312 312 313 313 314 314 315 316 317 317 318 319 320 321 321 322 322 323 323 vi

Analysis 13.15. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 15 Adverse event: Bloating. . . . . . . . . . . . . . . . . . . . . . . Analysis 13.16. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 16 Adverse event: loose stools. . . . . . . . . . . . . . . . . . . . . . Analysis 14.1. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 1 H. pylori persistence, subgroup by regimen. . . . . . . . . . . . . . . . . . . . . . . . . Analysis 14.2. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 2 H. pylori persistence, subgroup by location. . . . . . . . . . . . . . . . . . . . . . . . . Analysis 14.3. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 3 H. pylori persistence, subgroup by baseline PUD or FD. . . . . . . . . . . . . . . . . . . . . Analysis 14.4. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 4 H. pylori persistence, subgroup by risk of bias: overall. . . . . . . . . . . . . . . . . . . . . . Analysis 14.5. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 5 Patients with adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 14.6. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 6 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . . . . . . . . Analysis 14.7. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 7 Adverse event: Diarrhoea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 14.8. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 8 Adverse event: Skin rash/itching. . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 14.9. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 9 Adverse event: Dizziness/drowsiness. . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 14.10. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 10 Adverse event: Abdominal discomfort. . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 14.11. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 11 Adverse event: Fever. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 14.12. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 12 Adverse event: Vomiting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 14.13. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 13 Adverse event: Fatigue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 14.14. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 14 Adverse event: Headache. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 14.15. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 15 Adverse event: Nausea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 15.1. Comparison 15 PPI + bismuth + two antibiotics quadruple therapy, 10 days versus 7 days, Outcome 1 H. pylori persistence, subgroup by regimens. . . . . . . . . . . . . . . . . . . . . . . . . Analysis 15.2. Comparison 15 PPI + bismuth + two antibiotics quadruple therapy, 10 days versus 7 days, Outcome 2 H. pylori persistence, subgroup by location. . . . . . . . . . . . . . . . . . . . . . . . . Analysis 15.3. Comparison 15 PPI + bismuth + two antibiotics quadruple therapy, 10 days versus 7 days, Outcome 3 H. pylori persistence, subgroup by baseline disease. . . . . . . . . . . . . . . . . . . . . . . Analysis 15.4. Comparison 15 PPI + bismuth + two antibiotics quadruple therapy, 10 days versus 7 days, Outcome 4 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . . . . . . . . Analysis 16.1. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 1 H. pylori persistence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 16.2. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 2 Patients with adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 16.3. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 3 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . . . . . . . . Analysis 16.4. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 4 Adverse events: nausea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 16.5. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 5 Adverse events: vomiting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

324 324 325 326 327 328 329 330 331 332 333 333 334 334 335 335 336 336 337 338 339 339 340 341 341 342 vii

Analysis 16.6. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 6 Adverse events: Stomach ache. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 16.7. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 7 Adverse events: diarrhoea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 16.8. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 8 Adverse events: glossitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 16.9. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 9 Adverse events: vaginitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 16.10. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 10 Adverse events: dysphagia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 16.11. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 11 Adverse events: dizziness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 16.12. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 12 Adverse events: unfitness/discomfort (patients reported). . . . . . . . . . . . . . . . . . . . Analysis 16.13. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 13 Adverse events: fatigue/weakness (patients reported). . . . . . . . . . . . . . . . . . . . . Analysis 17.1. Comparison 17 PPI + three antibiotics quadruple therapy, 10 days versus 7 days, Outcome 1 H. pylori persistence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 17.2. Comparison 17 PPI + three antibiotics quadruple therapy, 10 days versus 7 days, Outcome 2 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . . . . . . . . . . . Analysis 18.1. Comparison 18 PPI dual therapy (PPI + one antibiotic) 14 days versus 7 days, Outcome 1 H. pylori persistence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 18.2. Comparison 18 PPI dual therapy (PPI + one antibiotic) 14 days versus 7 days, Outcome 2 Patients with adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 19.1. Comparison 19 PPI dual therapy (PPI + one antibiotic), 10 days versus 7 days, Outcome 1 H. pylori persistence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 19.2. Comparison 19 PPI dual therapy (PPI + one antibiotic), 10 days versus 7 days, Outcome 2 Patients with adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 19.3. Comparison 19 PPI dual therapy (PPI + one antibiotic), 10 days versus 7 days, Outcome 3 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . . . . . . . . . . . Analysis 20.1. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 1 H. pylori persistence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 20.2. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 2 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 20.3. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 3 Adverse event: Anorexia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 20.4. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 4 Adverse event: Nausea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 20.5. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 5 Adverse event: Vomiting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 20.6. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 6 Adverse event: Diarrhoea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 20.7. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 7 Adverse event: Constipation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 20.8. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 8 Adverse event; Dizziness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 20.9. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 9 Adverse event: Headache. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 20.10. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 10 Adverse event: Fatigue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 20.11. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 11 Adverse event: Unpleasant taste. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

342 343 343 344 344 345 345 346 346 347 348 348 349 350 350 351 352 352 353 353 354 354 355 355 356 356 viii

Analysis 20.12. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 12 Adverse event: Dry mouth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 20.13. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 13 Adverse event: Anal itching. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 20.14. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 14 Adverse event: Dysuria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 20.15. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 15 Adverse event: Urticaria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 21.1. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 1 H. pylori persistence, subgroup by regimen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 21.2. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 2 Patients with adverse event. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 21.3. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 3 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 21.4. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 4 Adverse event: Epigastric pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 21.5. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 5 Adverse event: Nausea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 21.6. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 6 Adverse event: Diarrhoea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 21.7. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 7 Adverse event: Vomiting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 21.8. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 8 Adverse event: Headache. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 21.9. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 9 Adverse event: Skin rash. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 21.10. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 10 Adverse event: Taste disturbance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 22.1. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 1 H. pylori persistence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 22.2. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 2 Patients with adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 22.3. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 3 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 22.4. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 4 Adverse event: Nausea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 22.5. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 5 Adverse event: Headache. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 22.6. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 6 Adverse event: Pruritus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 22.7. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 7 Adverse event: Allergic dermatitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 22.8. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 8 Adverse event: Conjunctivitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 22.9. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 9 Adverse event: Asthenia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 23.1. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 1 H. pylori persistence, subgroup by regimen. . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 23.2. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 2 H. pylori persistence, subgroup by location. . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 23.3. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 3 H. pylori persistence, subgroup by baseline PUD or FD. . . . . . . . . . . . . . . . . . . . . . . Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

357 357 358 358 359 360 360 361 361 362 362 363 363 364 364 365 366 366 367 367 368 368 369 369 370 371 ix

Analysis 23.4. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 4 H. pylori persistence, subgroup by risk of bias: allocation concealment. . . . . . . . . . . . . . . . . . Analysis 23.5. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 5 H. pylori persistence, subgroup by risk of bias: overall. . . . . . . . . . . . . . . . . . . . . . . . Analysis 23.6. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 6 Patients with adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 23.7. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 7 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . . . . . . . . . . . Analysis 23.8. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 8 Adverse event: Diarrhoea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 23.9. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 9 Adverse event: Nausea or Vomiting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 23.10. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 10 Adverse event: Headache. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 23.11. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 11 Adverse event: Taste alteration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 23.12. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 12 Adverse event: Epigastric discomfort. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 23.13. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 13 Adverse event: Dizziness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 24.1. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 1 H. pylori persistence, subgroup by regimen. . . . . . . . . . . . . . . . . . . . . . . . Analysis 24.2. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 2 Patients with adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 24.3. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 3 Patients discontinuing treatment due to adverse events. . . . . . . . . . . . . . . . . . . . Analysis 24.4. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 4 Adverse event: Nausea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 24.5. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 5 Adverse event: Vomiting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 24.6. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 6 Adverse event: Metalic taste or bad taste. . . . . . . . . . . . . . . . . . . . . . . . . Analysis 24.7. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 7 Adverse event: Heartburn. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 24.8. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 8 Adverse event: Diarrhoea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 24.9. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 9 Adverse event: Stomach pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 24.10. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 10 Adverse event: Burning sensation in the oesophagus. . . . . . . . . . . . . . . . . . . . . Analysis 24.11. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 11 Adverse event: Burning sensation in the mouth. . . . . . . . . . . . . . . . . . . . . . . Analysis 24.12. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 12 Adverse event: Dysphagia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 24.13. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 13 Adverse event: Burping. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 24.14. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 14 Adverse event: Anorexia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 24.15. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 15 Adverse event: Dizziness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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DECLARATIONS OF INTEREST . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW NOTES . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . .

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[Intervention Review]

Optimum duration of regimens for Helicobacter pylori eradication Yuhong Yuan1 , Alex C Ford2 , Khurram J Khan1 , Javier P Gisbert3 , David Forman4 , Grigorios I Leontiadis1 , Frances Tse1 , Xavier Calvet5 , Carlo Fallone6 , Lori Fischbach7 , Giuseppina Oderda8 , Franco Bazzoli9 , Paul Moayyedi1 1

Department of Medicine, Division of Gastroenterology, McMaster University, Hamilton, Canada. 2 Department of Academic Medicine, St. James’s University Hospital, Leeds, UK. 3 Gastroenterology Unit, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IP), and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain. 4 International Agency for Research on Cancer, Lyon, France. 5 Servei de Malalties Digestives, Hospital de Sabadell & Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Sabadell, Spain. 6 Faculty of Medicine, McGill University Health Centre, Montreal, Canada. 7 Department of Epidemiology, University of Arkansas for Medical Sciences, Little Rock, AR, USA. 8 Paediatric Endoscopy Units, Universita del Piemonte Orientale, Novara, Italy. 9 Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi di Bologna, Bologna, Italy Contact address: Yuhong Yuan, Department of Medicine, Division of Gastroenterology, McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4K1, Canada. [email protected].

Editorial group: Cochrane Upper GI and Pancreatic Diseases Group. Publication status and date: New, published in Issue 12, 2013. Review content assessed as up-to-date: 23 February 2012. Citation: Yuan Y, Ford AC, Khan KJ, Gisbert JP, Forman D, Leontiadis GI, Tse F, Calvet X, Fallone C, Fischbach L, Oderda G, Bazzoli F, Moayyedi P. Optimum duration of regimens for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD008337. DOI: 10.1002/14651858.CD008337.pub2. Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background The optimal duration for Helicobacter pylori (H. pylori) eradication therapy is controversial, with recommendations ranging from 7 to 14 days. Several systematic reviews have attempted to address this issue but have given conflicting results and limited their analysis to proton pump inhibitor (PPI), two antibiotics (PPI triple) therapy. We performed a systematic review and meta-analysis to investigate the optimal duration of multiple H. pylori eradication regimens. Objectives The primary objective was to assess the relative effectiveness of different durations (7, 10 or 14 days) of a variety of regimens for eradicating H. pylori. The primary outcome was H. pylori persistence. The secondary outcome was adverse events. Search methods The Cochrane Library, MEDLINE, EMBASE, and CINAHL were searched up to December 2011 to identify eligible randomised controlled trials (RCTs). We also searched the proceedings of six conferences from 1995 to 2011, dissertations and theses, and grey literature. There were no language restrictions applied to any search. Selection criteria Only parallel group RCTs assessing the efficacy of one to two weeks duration of first line H. pylori eradication regimens in adults were eligible. Within each regimen, the same combinations of drugs at the same dose were compared over different durations. Studies with at least two arms comparing 7, 10, or 14 days were eligible. Enrolled participants needed to be diagnosed with at least one positive Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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test for H. pylori on the basis of a rapid urease test (RUT), histology, culture, urea breath test (UBT), or a stool antigen test (HpSA) before treatment. Eligible trials needed to confirm eradication of H. pylori as their primary outcome at least 28 days after completion of eradication treatment. Trials using only serology or a polymerase chain reaction (PCR) to determine H. pylori infection or eradication were excluded. Data collection and analysis Study eligibility and data extraction were performed by two independent review authors. Data analyses were performed within each type of intervention, for both primary and secondary outcomes. The relative risk (RR) and number needed to treat (NNT)/number needed to harm (NNTH) according to duration of therapy were calculated using the outcomes of H. pylori persistence and adverse events. A random-effects model was used. Subgroup analyses and sensitivity analyses were planned a priori. Main results In total, 75 studies met the inclusion criteria. Eight types of regimens were reported with at least two comparative eligible durations. They included: PPI + two antibiotics triple therapy (n = 59), PPI bismuth-based quadruple therapy (n = 6), PPI + three antibiotics quadruple therapy (n = 1), PPI dual therapy (n = 2), histamine H2 -receptor antagonist (H2 RA) bismuth quadruple therapy (n = 3), H2 RA bismuth-based triple therapy (n = 2), H2 RA + two antibiotics triple therapy (n = 3), and bismuth + two antibiotics triple therapy (n = 2). Some studies provided data for more than one regimen or more than two durations. For the PPI triple therapy, 59 studies with five regimens were reported: PPI + clarithromycin + amoxicillin (PCA); PPI + clarithromycin + a nitroimidazole (PCN); PPI + amoxicillin + nitroimidazole (PAN); PPI + amoxicillin + a quinolone (PAQ); and PPI + amoxicillin + a nitrofuran (PANi). Regardless of type and dose of antibiotics, increased duration of PPI triple therapy from 7 to 14 days significantly increased the H. pylori eradication rate (45 studies, 72.9% versus 81.9%), the RR for H. pylori persistence was 0.66 (95% CI 0.60 to 0.74), NNT was 11 (95% CI 9 to 14). Significant effects were seen in the subgroup of PCA (34 studies, RR 0.65, 95% CI 0.57 to 0.75; NNT 12, 95% CI 9 to 16); PAN (10 studies, RR 0.67, 95% CI 0.52 to 0.86; NNT = 11, 95% CI 8 to 25); and in PAQ (2 studies, RR 0.37, 95% CI 0.16 to 0.83; NNT 3, 95% CI 2 to 10); but not in PCN triple therapy (4 studies, RR 0.87, 95% CI 0.71 to 1.07). Significantly increased eradication rates were also seen for PPI triple therapy with 10 versus 7 days (24 studies, 79.9% versus 75.7%; RR 0.80, 95% CI 0.72 to 0.89; NNT 21, 95% CI 15 to 38) and 14 versus 10 days (12 studies, 84.4% versus 78.5%; RR 0.72, 95% CI 0.58 to 0.90; NNT 17, 95% CI 11 to 46); especially in the subgroup of PAC for 10 versus 7 days (17 studies, RR 0.80, 95% CI 0.70 to 0.91) and for 14 versus 10 days (10 studies, RR 0.69, 95% CI 0.52 to 0.91). A trend towards increased H. pylori eradication rates was seen with increased duration of PCN for 10 versus 7 days, and of PAN for 10 versus 7 days and 14 versus 10 days, though this was not statistical significant. The proportion of patients with adverse events, defined by authors, was marginally significantly increased only between 7 days and 14 days (15.5% versus 19.4%; RR 1.21, 95% CI 1.06 to 1.37; NNTH 31, 95% CI 18 to 104) but not for other duration comparisons. The proportion of patients discontinuing treatment due to adverse events was not significantly different between treatment durations. Only limited data were reported for different durations of regimens other than PPI triple therapy. No significant difference of the eradication rate was seen for all regimens according to different durations except for H2 RA bismuth quadruple therapy, where a significantly higher eradication rate was seen for 14 days versus 7 days, however only one study reported outcome data. Authors’ conclusions Increasing the duration of PPI-based triple therapy increases H. pylori eradication rates. For PCA, prolonging treatment duration from 7 to 10 or from 10 to 14 days is associated with a significantly higher eradication rate. The optimal duration of therapy for PCA and PAN is at least 14 days. More data are needed to confirm if there is any benefit of increasing the duration of therapy for PCN therapy. Information is limited for regimens other than PPI triple therapy; more studies are needed to draw meaningful conclusions for optimal duration of other H. pylori eradication regimens.

PLAIN LANGUAGE SUMMARY Ideal length of treatment for Helicobacter pylori (H. pylori) eradication The ideal duration of therapy for H. pylori eradication is controversial, with recommendations ranging from 7 to 14 days. A proton pump inhibitor (PPI) plus two antibiotics is the most commonly used first treatment to remove H. pylori infection. Current data suggest that increasing the length of treatment to 14 days of a PPI plus amoxicillin and clarithromycin or amoxicillin and a nitroimidazole Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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significantly increases the eradication rate, while increasing the adverse events by a small amount. Based on the overall evidence, the ideal length of treatment with a PPI plus amoxicillin and clarithromycin is at least 14 days.


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S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

PPI triple therapy for 14 days versus 7 days for Helicobacter pylori eradication Patient or population: patients with Helicobacter pylori infection Settings: outpatient clinic Intervention: PPI based triple therapy for 14 days Comparison: 7 days treatment Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Corresponding risk

7 days treatment

PPI based triple therapy for 14 days

H. pylori persistence, re- Moderate gardless of regimen and 26 per 100 dose

H. pylori persistence, Moderate PCA subgroup 24 per 100

H. pylori persistence, Moderate PCN subgroup 33 per 100

H. pylori persistence, Moderate PAN subgroup 26 per 100

Relative effect (95% CI)

No of Participants (studies)

Quality of the evidence (GRADE)

Comments

RR 0.66 (0.6 to 0.74)

7722 (45 studies)

⊕⊕⊕ moderate1,2,3

NNT 11 (95% CI 9 to 14)

RR 0.65 (0.57 to 0.75)

5801 (34 studies)


NNT 12 (95% CI 9 to 16)

RR 0.87 (0.71 to 1.07)

688 (4 studies)

⊕⊕

low4,5,6,7

RR 0.67 (0.52 to 0.86)

1066 (10 studies)


17 per 100 (15 to 19)

16 per 100 (14 to 18)

28 per 100 (23 to 35)

18 per 100 (14 to 23)

NNT 11 (95% CI 8 to 25)

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H. pylori persistence, Moderate PAQ subgroup 55 per 100

Patients with adverse Moderate events, regardless of 17 per 100 regimen and dose

RR 0.37 (0.16 to 0.83)

167 (2 studies)

⊕⊕

low10,11

NNT 3 (95% CI 2 to 10)

RR 1.2 (1.06 to 1.37)

3971 (25 studies)

⊕⊕⊕ moderate1,5

NNTH 31 (95% CI 18 to 104)

20 per 100 (9 to 46)

20 per 100 (18 to 23)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; NNT : number needed to treat; NNTH: number needed to treat for an additional harmful outcome GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1

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Most information is obtained from studies with high risk or unclear risk of bias. Especially, most studies were not blinded for performance or outcome assessment. Open label studies ay lead to bias in adverse event reporting, different compliance, and medications out of study regimens. However, the assessment for H. pylori eradication as an objective outcome is less likely to be impacted by the open-label design compared to adverse events. 2 There is moderate by significant heterogeneity among studies. However, the heterogeneity can be explained by regimen, geographic location, baseline disease and risk of bias. Subgroup analyses and sensitivity analyses suggest prolonged treatment duration increase H. pylori eradication. Therefore, the quality of evidence is not downgraded for inconsistency/heterogeneity. 3 The assessment of the funnel plot asymmetry and results of the tests for funnel plot asymmetry indicated that publication bias or other small study effects may be present. It is possible that studies with non-significant results were not published, or potential poor methodological quality leading to inflated effects in smaller studies. In addition, the value of the tests for asymmetry reduced because there is significant heterogeneity between studies.The slope of the coefficient is low (not much greater than 1), therefore, the clinical importance of this publication bias or small-study effects is likely to be small, and the quality of evidence is mostly downgraded for publication bias. 4 When all risk domains were considered, only one study was considered as unclear risk of bias and the remaining three studies were considered as high risk of bias. 5 There is no significant heterogeneity among studies. 6 Only four studies were eligible for this comparison, although no significant treatment effect is shown, 95% confidence interval around the pooled estimate of effect includes both 1) no effect and 2) appreciable benefit. Further research is likely to change the estimate. 7 Fewer than 10 studies were included in this comparison, therefore, no test for funnel plot asymmetry was performed.


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When all risk domains were considered, stix studies was considered as high risk and four were considered as unclear risk of bias. The overview of the funnel plot and results of the tests for funnel plot asymmetry indicated that there was no evidence of publication bias or other small-study effects for this comparison 10 Both studies were considered high risk of bias, one study was high risk for randomisation and incomplete outcome data and the other study was high risk for blinding of participants and personnel. 11 Only two studies were eligible for this comparison, total sample size was small. Although significant treatment effect is shown, further research is likely to change the estimate.

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BACKGROUND A list of abbreviations is included in the Published notes section.

Description of the condition Helicobacter pylori (H. pylori) infects 7% to 87% of adults (de Martel 2006; Ford 2010a) depending on the population studied. H. pylori is more common in developing countries and over 50% of the world’s population is infected (Hunt 2011). H. pylori is associated with a wide range of upper gastrointestinal diseases, including peptic ulcer disease (PUD) and gastric cancer. The latest Maastricht IV Consensus (Malfertheiner 2012a) has reconfirmed the strong recommendation for H. pylori eradication for infected patients with PUD (Ford 2004) and mucosa-associated lymphoid tissue (MALT) lymphoma (Kato 2011), and for those with functional dyspepsia (Moayyedi 2000; Moayyedi 2003). The group also recommended H. pylori eradication in H. pylori positive first degree relatives of patients with gastric cancer as a prevention strategy. Other indications include patients with previous gastric neoplasia, patients with a risk of gastritis, patients with chronic gastric acid inhibition for more than one year, patients with strong environmental risk factors for gastric cancer (Gonzalez 2011), and H. pylori-positive patients with a fear of gastric cancer. It is suggested that a test-and-treat strategy is appropriate for uninvestigated dyspepsia in populations where theH. pylori prevalence is ≥ 10% (Talley 2005b). Infected patients that have a peptic ulcer bleed should be offered H. pylori eradication therapy to reduce the risk of rebleeding (Gisbert 2012; Laine 2012; Sanchez-Delgado 2011). H. pylori eradication reduces the risk of complicated and uncomplicated gastroduodenal ulcers associated with either non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (ASA) use; and it is mandatory before starting NSAIDs in patients with a peptic ulcer history. Furthermore, some have suggested that H pylori should be sought and eradicated in unexplained iron deciency anaemia, idiopathic thrombocytopenic purpura (Savarino 2011), and vitamin B12 deficiency. The second Asia-Pacific consensus guideline as well as the Maastricht IV Consensus recommended a population-based screen-and-treat strategy for H. pylori in communities with a high incidence of gastric cancer as an effective strategy for gastric cancer prevention (Fock 2009; Malfertheiner 2012a; Moayyedi 2000).

ment; while PPI-clarithromycin-metronidazole (PCM) and PPIclarithromycin-amoxicillin (PCA) regimens are considered to be equivalent (Malfertheiner 2012a). Bismuth-containing quadruple treatment is an alternative, especially in areas of high clarithromycin resistance. If this regimen is not available, sequential treatment or a non-bismuth quadruple treatment is recommended (Malfertheiner 2012a). Some other regimens may still be used as first line therapies in parts of the world due to local availability, cost, or resistance to antibiotics, ethnicity, local effectiveness, etc. The regimens that reported different durations and which were included in our review included: PPI + two antibiotics triple therapy, PPI bismuth-based quadruple therapy, PPI + three antibiotics quadruple therapy, PPI dual therapy, histamine H2 -receptor antagonist (H2 RA) bismuth quadruple therapy, H2 RA bismuthbased triple therapy, H2 RA + two antibiotics triple therapy, and bismuth + two antibiotics triple therapy. Given the wide indications for H. pylori eradication, the optimum duration of therapy is important; however, this remains controversial. Although international guidelines have recommended treatment durations of at least seven days, different optimum durations are recommended in different regions. In previous European (Malfertheiner 2007), Asian-Pacific (Asaka 2010; Fock 2009; Lam 1998), and Canadian (Hunt 1998; Hunt 1999) guidelines, PPIbased triple therapy has been suggested for at least seven days; whilst American guidelines recommend that PPI-based triple regimens are given for 10 or 14 days (Chey 2007; Howden 1998; Talley 2005a). Bismuth-based quadruple therapy is an alternative first line regimen and is generally recommended for 10 to 14 days (Chey 2007; Hunt 2004; Malfertheiner 2007; Talley 2005a). In the recent World Gastroenterology Organisation (WGO) Global guideline for developing countries, the suggestion for duration is not conclusive, “A longer treatment duration may increase eradication rates, but remains controversial: studies suggest an increase to 14 days instead of 7 days. Cost considerations and compliance issues may still favour 7-day therapy. Some groups suggest treatment for 10 days” (Hunt 2011). On the other hand, prolonged treatment duration is more expensive, and may lead to increased drug-related side effects and poor compliance (Ables 2007). It is unclear how much benefit is gained or if there are any more adverse effects by increasing the duration from 10 days to 14 days.

How the intervention might work Description of the intervention The most commonly used H. pylori eradication regimen is a triple therapy comprising a proton pump inhibitor (PPI) plus two antibiotics used twice daily (bid). Commonly, clarithromycin is used together with amoxicillin or a nitroimidazole (metronidazole or tinidazole) (Gisbert 2007; Hunt 2011). In areas of low clarithromycin resistance, clarithromycin-containing treatments are recommended for first line empirical treat-

Current first line triple therapies eradicate H. pylori in only 60% to 80% of patients whilst an optimal treatment should be successful in ≥ 90% patients. Factors such as choice of drug, dose, dosing intervals, and treatment duration influence the success rate (Graham 2010). In particular, increased treatment duration should be associated with increased eradication rates as the organism is exposed to the antibiotics for a longer time period. Based on several published meta-analyses, the most recent Maastricht IV Consensus suggests that “Extending the duration of PPI-clarithromycin-


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containing triple treatment from 7 to 10 to 14 days improves the eradication success by approximately 5% and may be considered” (Malfertheiner 2012a). There are three published meta-analyses on the optimum duration for PPI triple therapy, with mixed results. The first meta-analysis of clarithromycin-based PPI triple therapy by Calvet et al in 2000 found that pooled 10- to 14-day therapies gave better results than seven days. However, in head-to-head comparisons, only 14day therapies were significantly better than seven days, with an increase in cure rates of 9% (Calvet 2000). A second meta-analysis by Ford et al in 2003 found that a 14-day PPI triple therapy was more effective than seven days by 12% (95% CI 7% to 17%), but found no significant difference between 10 days and seven days (Ford 2003). Based on this reference, the European Helicobacter Study Group reached a consensus in the Maastricht III consensus report that a 14-day rather than a seven-day treatment had an advantage in terms of treatment success, but that a seven-day treatment may be acceptable when local studies show that it is effective (Malfertheiner 2007) because it is a valid duration in numerous European countries (Mégraud 2005). There are recent randomised controlled trials (RCTs) published after the previous two meta-analyses, and we therefore planned an updated systematic review to investigate the optimum duration of all H. pylori eradication regimens. Since the development of this protocol, a third meta-analysis was published by a group in Italy which included 21 studies of first line PPI-based triple therapy (Fuccio 2007). They included nine more studies than Ford 2003, and concluded that extending triple therapy beyond seven days is unlikely to be a clinically useful strategy. The relative risk (RR) for eradication using amoxicillin-containing triple therapy was 1.05 (95% CI 1.01 to 1.10) for 7 versus 10 days and 1.07 (95% CI 1.02 to 1.12) for 7 versus 14 days. No significant difference was seen for metronidazole-containing therapy, and no significant difference was seen for seven versus 14 days for function dyspepsia (FD) and PUD subgroups (Fuccio 2007). The conclusion of this meta-analysis was in contrast with the previous two, and its publication generated a lot of interest as well as some disagreement with the conclusions (Calvet 2008). There are three meta-analyses on this topic published only as conference proceedings (Flores 2010; Jung 2008; Kim 2001). They included nine, 10, and 26 studies, respectively. Two of them only included studies published in Korean journals (Jung 2008; Kim 2001). We contacted the authors but we could not obtain the primary studies. The later abstract only compared PPI triple therapy for 14 versus 7 days and 10 versus 7 days (Flores 2010). The potential sources of treatment failure include antibiotic resistance, poor compliance, short duration of therapy, and drug-related side effects (Vilaichone 2006; Wolle 2007). Extension of the PPI triple regimen duration to 14 days, addition of a third antibiotic, or sequential therapy (that is, a PPI and amoxicillin for the first five days followed by a triple therapy including a PPI and two antibiotics for the remaining five days) might decrease treatment

failure, but all these strategies require further research before an ’optimum eradication strategy’ can be recommended (Vilaichone 2006). Many experts believe that to improve eradication rates, shorter durations should no longer be recommended. It is even suggested that when evaluating new regimens, the highest practical doses for the longest reasonable duration, such as 14 days, should be employed initially (Graham 2010). Although PPI triple therapy as first choice H. pylori treatment is recommended worldwide, it is also recognized that the choice of antibiotics may differ based on local patterns of antibiotic resistance, local economic status, and antibiotic availability. The golden rule for choice of treatment is only to use what works locally (Graham 2010). Therefore, the decision to treat for one or two weeks should also depend on the locally validated experience (Fock 2008).

Why it is important to do this review We noticed that all previous systematic reviews and meta-analyses focused exclusively on standard dose PPI triple therapy, and no systematic review has looked at the effect of duration on eradication efficacy in other regimens such as the bismuth-containing therapy, H2 RA or PPI quadruple therapy, or the use of antibiotics other than clarithromycin, amoxicillin, and a nitroimidazole. In addition, the search for eligible RCTs might have been incomplete in the previous studies. For example, a previous meta-analysis (Fuccio 2007) only included English language RCTs and searched three databases and three conference proceedings, several eligible studies were not identified according to their own inclusion criteria (Yuan 2009); we also identified some studies which were mistakenly included or excluded. Furthermore, in our preliminary search we identified several RCTs which were not included in the previous meta-analyses, and several RCTs which were subsequently published. This is consistent with the observation that errors can occur in systematic reviews and it is important to independently validate the results (Ford 2010b). We therefore conducted a systematic review of RCTs addressing the optimum duration of all H. pylori eradication therapies by using more databases, optimised search strategies, and applying the rigorous techniques recommended by The Cochrane Collaboration. This systematic review was developed from an ongoing Cochrane systematic review of all H. pylori eradication therapies (Forman 2000).

OBJECTIVES

Primary objective To assess the relative effectiveness of one to two weeks’ duration (14 versus seven days, 10 versus seven days, 14 versus 10 days) of different treatment regimens for eradicating H. pylori.


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Secondary objective To compare the incidence of adverse effects associated with different treatment durations of H. pylori eradication therapy.

We also excluded trials with participants: diagnosed as H. pylori positive solely on the basis of serology or polymerase chain reaction (PCR); who had previously been treated with an eradication therapy; or diagnosed exclusively using other methods to determine H. pylori infection or eradication. We excluded studies that recruited less than 75% adults (aged 16 years or over, based on the participants’ baseline characteristics).

METHODS Types of interventions

Criteria for considering studies for this review

Types of studies We considered only parallel group randomised controlled trials (RCTs) eligible for inclusion in the review without language restriction.

Types of participants We considered randomised trials eligible for inclusion in the review if they recruited individuals diagnosed as positive for H. pylori, with at least one confirmatory test, on the basis of a rapid urease test (RUT), histology or culture of an endoscopic biopsy sample, urea breath test (UBT), or monoclonal stool antigen tests (HpSA). We included trials regardless of the presenting symptoms and disease, except those which included any patients who presented with an active bleeding peptic ulcer. At least 75% of the participants must have been adults (aged 16 years or over). Studies were eligible if the minimum age of the participant was at least 16 years old. Some studies did not provide information on the participants’ minimum age, or the minimum age was less than 16 years without stating the percentage of participants less than 16 years old. We tried to contact the authors for missing details. If the study did not specify it was for paediatric patients and we could not obtain additional data from authors, we judged that the majority of the study participants were adults, based on the following a priori criteria. • If the mean age and SD of the mean were provided, then the mean age - 2* SD was calculated. If this value was greater than 16 years, then we were confident that that > 95% of participants were older than 16 years of age. If the mean age - 2* SD was less than 16 years, but mean age - 1* SD > 16 years, then we were confident that more than 75% of participants were greater than 16 years of age, based on the normal distribution assumption of the ages. • Some studies only provided mean age. If the mean age was greater than 40 years, and none of the authors were affiliated with a paediatric department in the byline, then we presumed that the major study population were adults; i.e., more than 75% of the participants were older than 16 years of age.

We included all trials comparing different durations of therapy for H. pylori eradication. Within each of these regimens, the same combinations of drugs at the same dose must have been compared over different durations, or at least have two arms that compared regimens between 7, 10 or 14 days. The following eradication regimens met the inclusion criteria and the trials reported analysable data. 1. PPI + two antibiotics triple therapy: i) a PPI (omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole) + two out of three of either a macrolide (clarithromycin or azithromycin or roxithromycin) or a nitroimidazole (metronidazole or tinidazole) or amoxicillin; ii) a PPI + a quinolone (ofloxacin, moxifloxacin, or levofloxacin, etc) + an antibiotic; iii) a PPI + two antibiotics other than those of 1a, 1b. 2. PPI bismuth-based quadruple therapy: PPI + bismuth salt (colloidal bismuth subcitrate (CBS) or bismuth subsalicylate (BSS)) + two antibiotics. 3. PPI + three antibiotics quadruple therapy. 4. PPI dual therapy: a PPI + one antibiotic. 5. H2 RA bismuth-based quadruple therapy: i) a H2 RA + bismuth salt + two antibiotics; ii) ranitidine bismuth citrate (RBC) + two antibiotics. 6. H2 RA bismuth-based triple therapy: RBC + one antibiotic. 7. H2 RA triple therapy: a H2 RA + two antibiotics. 8. Bismuth triple therapy: a bismuth salt + two antibiotics. We excluded studies that compared different durations other than 7, 10 or 14 days if they did not include at least two of the following durations: 7, 10 and 14 days. We also excluded studies if different types of drug or drug does were used in the comparison treatment arms. We excluded studies that compared treatment duration for sequential therapy from this review, because the antibiotics used are different for two different sequences within the same regimen. We also excluded trials if the sample size for the intention-totreat (ITT) analysis was not available and only the per protocol (PP) analysis was provided. The decision to exclude studies that did not report ITT results (and did not allow for estimation of ITT results) was based on the empirical evidence in studies on H. pylori eradication the PP eradication rates are consistently higher that the ITT rates. Therefore the inclusion of studies that only provided PP results would introduce bias by skewing the results towards higher efficacy.


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Types of outcome measures We included trials if they reported evidence of eradication of H. pylori as their primary outcome. Trials were eligible if H. pylori eradication was confirmed using RUT, histology or culture of an endoscopic biopsy sample, UBT, or a HpSA test at least four weeks after completion of treatment. Assessment by serology test or PCR alone was not satisfactory. We also collected reports of adverse effects, noting the proportion of participants: with adverse events; who discontinued treatment due to adverse events; with upper gastrointestinal disturbances (e.g., nausea, vomiting, dyspepsia); with lower gastrointestinal disturbances (e.g., diarrhoea, constipation); with dermatological problems (e.g., rash, dermatitis); and with systemic effects (fever, headache, dizziness), etc. Primary outcomes

The relative effectiveness of one to two weeks’ duration (14 versus7 days, 10 versus 7 days, 14 versus 10 days) of different regimens in eradicating H. pylori. Secondary outcomes

The incidence of adverse effects associated with different durations of H. pylori eradication therapy.

• EMBASE (1980 to December 2011) by Ovid (Appendix 3); • CINAHL (Cumulative Index to Nursing & Allied Health Literature) (1982 to December 2011) (Appendix 4). We also searched the following grey literature databases using free text terms: • ProQuest dissertations and theses; • GrayLitNetwork (http://www.osti.gov/graylit/), retired on 31 October 2007 (accessed in July 2007) and then re-launched as Science Accelerator (http://www.scienceaccelerator.gov/); • New York Academic of Medline Library Gray literature collection (http://www.nyam.org/library/pages/ grey_literature_report); • SIGLE (System for Information on Grey Literature in Europe) (http://www.cf.ac.uk/insrv/eresources/databases/ sigle.html) (note this database covers from 1980 to March 2005 and is no longer updated) and Opengrey (http:// www.opengrey.eu/) (1992 to December 2011); • EUFORGEN (European Forest Genetic Resources Programme) database on grey literature (http:// www.bioversityinternational.org/Networks/Euforgen/ Euf_Grey_Literature.asp); • Canadian Evaluation Society unpublished literature bank (2002 to December 2011) (http://www.evaluationcanada.ca/ site.cgi?s=6&ss=8&_lang=EN). Searching other resources

Search methods for identification of studies We undertook the principal electronic search according to the Cochrane Upper Gastrointestinal and Pancreatic Diseases (UGPD) Review Group module (published on The Cochrane Library) (Forman 2009). Electronic searches The standard Cochrane search strategy filter for identifying RCTs was applied to all searches. We performed the complementary search by using several optimised search strategies for identifying RCTs in MEDLINE and EMBASE, which has been developed by the McMaster University Hedges team (Haynes 2005; Wilczynski 2007; Wong 2006) and by UK information specialists (Glanville 2006) with improved precision and parsimony after the 2002 Cochrane highly sensitive search strategy (HSSS). We undertook electronic searches of published electronic databases using a combination of subject headings and text words relating to eradication of H. pylori. We searched the following databases: • Cochrane Central Register of Controlled Trials (CENTRAL) and Cochrane Database of Systematic Reviews (Appendix 1) (The Cochrane Library 2011, Issue 4); • MEDLINE (1950 to December 2011) by Ovid (Appendix 2);

Abstracts

We searched abstracts from the following conference proceedings up to December 2011: • American Gastroenterological Association (AGA) congresses from Digestive Diseases Week (DDW) (1995 to 2011) (published in Gastroenterology); • Annual Scientific Meeting of the American College of Gastroenterology (ACG) 2001 to 2011 (published in American Journal of Gastroenterology); • British Society of Gastroenterology (BSG) annual meeting 1995 to 2011 (published in Gut); • European Gastroenterology Week (UEGW) congresses of 1995 to 2011 (published in Gut or United European Gastroenterology Journal or abstract CDs); • European Helicobacter Study Group (EHSG) congresses 2002 to 2011 (published on the website (http:// www.helicobacter.org) and in Helicobacter); • The World Congress of Gastroenterology (WCOG) 2002 (published in Journal of Gastroenterology and Hepatology), WCOG 2005 (published in Canadian Journal of Gastroenterology), and WCOG 2009 (published in Gut); • ProceedingsFirst database via FirstSearch OCLC (http:// www.oclc.org/) (1993 to 2011).


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We performed a recursive search of the bibliography of retrieved papers. Authors of trials published only as abstracts were contacted and asked to contribute full data sets or completed papers. We excluded abstracts if key information for efficacy was not available (for example, H. pylori eradication rate, H. pylori infection assessment methods, etc). Searches of personal databases

Several review authors (Drs Moayyedi, Gisbert, Unge, Chiba, Laheij, Hunt, Harris, Fischbach) have collated personal databases of articles relating to H. pylori eradication, which we also searched for relevant trials. Correspondence

We contacted relevant pharmaceutical companies (AstraZeneca, Wyeth Pharmaceuticals, Abbott, Nycomed, Glaxo Wellcome) and asked them to contribute data or information about all relevant trials. We also contacted field experts registered with the Cochrane UGPD review group for unpublished studies.

Data collection and analysis

Selection of studies We collated the study citations selected for inclusion in a single database. One investigator (YY) checked the eligibility of the included studies and excluded duplicate citations and articles unlikely to be of relevance by scanning their titles and abstracts. Two investigators (YY and AF) independently checked the study eligibility by reviewing the complete reports of all selected articles. A decision whether to include the trial was made for each article independently, according to the pre-stated eligibility criteria. We resolved disagreements by discussion with a third investigator. When duplicate publications or overlapping databases were suspected, we selected the most comprehensive report. Data extraction and management We extracted and recorded data on a specially developed and tested data extraction form. All data were extracted independently by YY and AF, or YY and KK). We resolved discrepancies by discussion and sought the opinion of the third investigator if there was any uncertainty. After data were entered in RevMan, two authors (JG and FB) were randomly assigned 20 studies to double-check data extraction and data entry. We recorded the following characteristics for each trial. • Details of participants including demographic characteristics (e.g., age, country or geographic area, source of recruitment), medical condition (PUD or FD or others) at

enrolment, H. pylori bacterial strain (if typed), and whether any mention was made regarding exclusion of treatment failures. • Details of the experimental and control eradication interventions including drugs, doses, schedules, duration, concomitant medication, and the use of a pre-treatment and post-treatment intervention. • Details of the methods of assessment of H. pylori both before and after treatment, noting the tests used and the timing in relation to treatment commencement and completion. Whether the antibiotic sensitivity and resistance was tested before and after eradication; if so, the methods used, definition of resistance, and the primary and secondary antibiotic resistance rate. • The number of participants allocated to each group, and the number who were H. pylori positive at outcome assessment. We extracted data from ITT analyses, and calculated the ITT sample if authors only reported their PP sample but provided randomisation and dropout information. We included participants in the ITT sample who did not receive the treatment (Montori 2001). • Definition of compliance and the compliance rate in the ITT sample. • The numbers incurring each (or any) of the listed adverse effects, type and severity. Number of participants who discontinued treatment because of adverse events. If possible, we calculated the adverse event rate based on the participant sample who had taken at least one pill, if reported by the authors. Otherwise, the adverse event rate would be underestimated using the ITT sample. • Eight domains of risk of bias: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data of H. pylori and adverse events, selective reporting, and other bias. • Miscellaneous details of the study including year of publication, format (abstract or journal article), source of financial support, and whether participants were paid. Assessment of risk of bias in included studies Two investigators (YY, KK) independently assessed the risk of bias of included studies based on the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Disagreement was resolved by discussion, or the opinion of the third investigator was sought. We assessed the components of quality using the criteria described below. We gave no quality score and we did not exclude any trials based on methodological quality. The individual risk of bias assessment items were planned to be used to explore sources of heterogeneity if significant heterogeneity between studies was shown (details below). Eight risk domains were assessed. A study was considered to have a low risk of bias, high risk of bias, or an unclear risk of bias if: all risk domains were assessed as a low risk of bias, at least one domain was assessed as high risk, or at least one domain was assessed as unclear risk without any high risk do-


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main, respectively. We used allocation concealment and low risk versus high risk versus unclear risk of bias in subgroup analysis with pooled effect size estimated. Random sequence generation (selection bias)

We classified a study as an RCT if it was described as randomised (this includes the use of words such as randomly, random, and randomisation, etc). We judged the study as low risk, high risk, and unclear risk according to the following. • Low risk, if the allocation sequence was generated by computer-generated random numbers, published random number table, coin tossing, shuffling cards or envelopes, or throwing dice. • Unclear risk, if the trial was described as randomised but the method used for generation of the allocation sequence was not described. • High risk, selection was based on patient numbers, birth dates, visit dates, or alternative allocation. • We excluded studies which described selection based on patient or clinical preference, or any selection mechanism that can not be described as random. We also excluded studies that did not state whether the treatment was randomly allocated. Allocation concealment (selection bias)

• Low risk, if trialists were unaware of the allocation of each participant before they were entered in the trial. Acceptable methods included: central telephone randomisation schemes, pharmacy-based schemes, sequentially numbered opaque sealed envelopes, or sequentially numbered drug containers of identical appearance. • Unclear risk, the authors did not report or provide a description of an allocation concealment approach that allowed for classification as concealed or not concealed. • High risk, when trialists may have been aware of the allocation of each participant before they entered the trial e.g., when allocation was based on patient data such as by date of birth, hospital case note number, visit dates, sealed envelopes that were not opaque, or a random number table that was not concealed from an investigator. Blinding of participants and personnel (performance bias)

• Low risk, if both patients and physicians were blinded to the treatment allocation; and it was unlikely that the blinding could have been broken. • Unclear risk, if no blinding information was available or insufficient information to permit a judgement of low risk or high risk. • High risk, if the authors defined it as an open study, or that no party was blinded. Either participants or some key study personnel were not blinded, and the non-blinding of others was likely to introduce bias.

Blinding of outcome assessment (detection bias)

• Low risk: outcome assessors were blinded to the assigned treatment arm. • Unclear risk: no information was provided for blinding of outcome assessment. • High risk: outcome assessors were not blinded to the assigned treatment arm. Adverse event as the outcome is likely to be influenced by lack of blinding. However, knowledge of the assigned intervention is unlikely to impact on H. pylori eradication assessment. Incomplete outcome data (attrition bias)

Attrition bias was assessed for H. pylori eradication and adverse events. • Low risk, if there were no missing outcome data; reasons for missing outcome data unlikely to be related to true outcome; missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; the proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate; missing data were imputed using appropriate methods. • Unclear risk, if insufficient reporting of attrition or exclusions to permit judgement of low risk or high risk (e.g., no reasons for missing data provided). • High risk, if reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; PP analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation. We noted the proportion of participants for which there were missing outcome data or who were excluded from the analysis for each arm of the trial, or both. In the ITT analyses, we assumed these participants to have failed therapy. We noted whether the analysis that was presented included all randomised participants (ITT approach). We recorded the authors’ definitions when they reported an ITT analysis. Due to the varied definitions of ITT by authors, we used the most accepted definition of ITT approach: all participants in the groups to which they were originally randomly assigned, regardless of whether they actually satisfied the entry criteria, whether the treatment was actually received, and with subsequent withdrawal or deviation from the protocol (Hollis 1999; Montori 2001). Whenever possible, we tried to retrieve information for all randomised participants. However, we included all studies that authors reported as having an ITT analysis (for example, some studies required participants to have taken at least one medication, or some studies required participants to have a second test con-


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firming H. pylori infection status after the randomisation, to be included in the ITT analysis). We used reported eradication data with more relaxed ITT definitions from these studies in the sensitivity analysis to see whether the conclusion changed compared to with the strict ITT analysis. We excluded all studies reporting PP analysis only if information was not available for ITT analysis (the primary authors explicitly stated they reported PP analysis data without providing the randomised sample size).

(for example, PAC seven days versus 14 days, seven days versus 10 days, and 10 days versus 14 days). We were only interested in the direct comparison between two treatment durations. We did not combine multiple groups to a single pair-wise comparison (for example, PAC seven days versus 10 + 14 days), so we did not use the same person twice in the same analysis. Therefore, no ’split of the share group’ was required. Dealing with missing data

Selective reporting (reporting bias)

• Low risk, if the published reports included all expected outcomes, including those that were pre-specified. • Unclear risk, if insufficient information to permit judgment of low risk or high risk. • High risk, if not all of the study’s pre-specified primary outcomes were reported; the primary outcome (H. pylori persistence) was reported using measurements, analysis methods, or subsets of the data that were not pre-specified; the primary outcome was not pre-specified or reported incompletely; or the study report failed to include results for a key outcome that would be expected to have been reported for such a study. Other bias

• Low risk, the study appears to be free of other sources of bias. • Unclear risk, there may be a risk of bias but there is either: insufficient information to assess whether an important risk of bias exists (e.g., limited information from a conference proceeding); or insufficient rationale or evidence that an identified problem introduces bias. • High risk, there is at least one important risk of bias; a potential source of bias related to the specific study design used; stopped early due to a data-dependent process (including a formal stopping rule); extreme baseline imbalance; has been claimed to have been fraudulent; or some other problem. Measures of treatment effect We performed data analyses within each of the eight types of interventions detailed above, for 14 versus seven days, 10 versus seven days, and 14 versus 10 days, both for the primary (H. pylori persistence) and second objectives (adverse events).

We attempted to contact authors for missing data. If no outcome data were available, we used the ITT approach, which included all randomised participants and presumed missing participants had failed eradication (worst case scenario). Assessment of heterogeneity We carried out a Chi² test for heterogeneity for each combined analysis where P < 0.10 indicated significant heterogeneity between studies (Higgins 2002), using a random-effects model. We also reported the I² statistic, which quantifies the heterogeneity by calculating the percentage of total variation across studies that was due to heterogeneity, an approach that is endorsed by The Cochrane Collaboration. We defined significant heterogeneity as I² > 25% based on the judgment that I² values of 25%, 50%, and 75%, represent low, moderate, and high heterogeneity, respectively (Higgins 2003). That is, either Chi² test P < 0.10 or I² > 25% were the criteria to consider heterogeneity as significant. Assessment of reporting biases Reporting bias was assessed visually by examining the relationship between the treatment effects and the standard error of the estimate using a funnel plot. Funnel plots were produced for the principal outcome for each duration comparison for primary outcome, when more than 10 studies were included in the analysis (Ioannidis 2007). Tests for funnel plot asymmetry were performed by the Begg, Egger and Harbord tests (Begg 1994; Egger 1997b; Harbord 2006) to investigate whether publication bias or other small study effects might have adversely affected the results. StatsDirect 2.7.7. (StatsDirect 2012) was used to generate the funnel plots. Data synthesis

Unit of analysis issues We included only standard design parallel group RCTs with binary outcomes (for example, H. pylori eradication). Cluster randomised trials, cross-over trials, and repeated measurement were not present for the type of RCT. However, multiple intervention groups were common (for example, PAC seven days versus 14 days versus 10 days) using the same study population. Participants in the same group were compared twice with two other groups

We performed data analyses within each of the eight types of interventions detailed above, for seven versus 10 days, 10 versus 14 days, and seven versus 14 days, both for the primary and second objectives. All outcomes included in this review were binary. Because all H. pylori eradication trials reported H. pylori eradication rate as their outcome, which is a term commonly used and easily understood by the clinicians, we reported the unweighted, pooled proportion


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with successful H. pylori eradication for each regimen before performing any comparative analysis. We expressed treatment effect for each trial as risk ratio (RR) together with the 95% confidence interval (CI), taking H. pylori persistence as the outcome. The RR describes the relative proportion of cases of failed eradication between each of the two regimens being compared. We chose RR as the summary statistic and the undesired outcome (H. pylori persistence) to calculate RR, because it is easily understood and interpreted by clinicians. Also, there is empirical evidence that RRs of the adverse outcome are more consistent than RRs of the non-event. We labelled the arm with longer duration as the treatment group and the arm with shorter duration as the control group in the analysis. We also considered the possible conclusions driven by different methods (Moayyedi 2004). We planned a priori that if the RR was very close to one, defined as any band of the 95% CI located within the range of 0.95 to 1.05 (exclusively), that we would perform a sensitivity analysis by calculating odds ratio (OR), and using a desirable outcome (H. pylori eradicated) as the event to calculate the RR (also named as relative benefit (RB) in evidencebased medicine (Glossary 2008)). We also summarized adverse effects with RR, comparing the rates of patients with adverse effects and patients that discontinued treatment due to adverse events. For PPI triple therapy, we first combined all PPI triple therapy regardless of the antibiotic regimens or doses used in the main analyses (for H. pylori persistence, patients with adverse events, and patients who discontinued therapy due to adverse events). We then made separate comparisons for each therapy length (14 versus seven days, 10 versus seven days, 14 versus 10 days) and for each broad type of eradication therapy (for example, PCA, PAN, PCN, PAQ triple therapy). For individual adverse events, we did not combine different treatment regimens. We attempted metaanalysis only if there were sufficient trials (≥ two) reporting the same comparison. We combined the RR using a random-effects model (MantelHaenszel method) (DerSimonian 1986; Egger 1997a). A fixedeffect model was used in the sensitivity analysis. There are several methods to calculate number needed to treat (NNT) and some have limitations (Altman 2002; Cates 2002; Moore 2002), causing us to be cautious when we interpreted the NNT (Hutton 2010). Many published meta-analyses do not provide the results or the methods they used. In this report we calculated the NNT for efficacy and number needed to treated for an additional harmful outcome (NNTH) for adverse events by using the formula NNT= 1 / (1 / (ACR x (1-RR)), and ACR (assumed control risk) was based on the pooled control event rate (CER) from the eligible studies, when a significant difference was found between two durations of treatment. We used the Cochrane Review Manager software (RevMan 2011) to carry out the analysis based on the ITT principle. Results are presented as forest plots, using a random-effects model.

Zero total event consideration

We included trials with no events. The current Revman software ( RevMan 2011) automatically replaces zero events with ’0.5’ events as a continuity correction to reduce bias when RRs or ORs are calculated (Bradburn 2007; Friedrich 2007; Sweeting 2004). Subgroup analysis and investigation of heterogeneity We performed pre-planned subgroup analyses for H. pylori persistence, regardless of whether significant heterogeneity was present, on the following subgroups. • Different PPI triple regimens. • Type and dose of antibiotics, dose of PPIs. • Geographic regions: western countries (European versus North or South America) versus Asia versus Africa versus others. • Type of disease at enrolment: PUD versus FD. • Risk of bias: concealment of allocation low risk versus high risk versus unclear risk; overall low risk versus high risk versus unclear risk of bias studies. Geographic regions were considered in the subgroup analyses because it is suggested that the H. pylori eradication rate by PPI triple therapy is influenced by patient CYP2C19 genotypes, and Asian patients have a higher prevalence of poor metabolizers than Caucasians (Furuta 2007). The efficacy of standard dose omeprazoleand lansoprazole-based PPI triple therapies has been found to be dependent on CYP2C19 genotype status (Zhao 2008). In addition, previous European and Asian guidelines had different duration recommendations than the American guidelines. Type and dose of antibiotics were also considered in the subgroup analyses because it is biologically plausible that increasing the dose of antibiotics could increase the H. pylori eradication rate, and clearly the type of antibiotic could have an impact on the treatment effect (Ford 2003; Huang 1999). As for baseline diseases, some studies suggested that patients with PUD have a greater H. pylori eradication rate compared to patients with FD, and this has biological plausibility based on several hypotheses (Gisbert 2001a); and the risk factors identified for eradication failure were different between patients with DU and patients with FD (Broutet 2003). A later meta-analysis did not reveal that FD patients respond to H pylori eradication treatments differently from those with PUD, although a trend exists with the seven-day PCA therapy (Huang 2008). However, the baseline effect between treatment durations is not known. Methodological deficiencies are known to affect the treatment effect size estimate. Allocation concealment was chosen as the most critical risk of bias item in the subgroup analyses because several studies had reported that intervention effect estimates were exaggerated in trials with inadequate allocation concealment versus trials with adequate allocation concealment (Gluud 2006; Jüni 2001; Wood 2008). In addition, we performed subgroup analyses for low risk versus high risk versus unclear risk of bias studies. We did not consider type of PPI in the subgroup analyses for PPI triple therapy because previous meta-analyses have shown


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that different PPIs are equivalent when used in PPI triple therapy (Buzás 2006; Vergara 2003). Double-dose, new-generation PPIs have similar H. pylori eradication rates and tolerability to omeprazole (Choi 2007), although more recent meta-analyses suggest esomeprazole and rabeprazole show better overall H. pylori eradication rates than first-generation PPIs (McNicholl 2012); and highdose PPI seems more effective than standard-dose PPI for curing H. pylori infection in seven-day triple therapy (Villoria 2008): the effect estimates were marginally significant (OR 1.32, 95% CI 1.01 to 1.73 for esomeprazole versus first-generation PPIs; OR 1.21, 95% CI 1.02 to 1.42 for rabeprazole versus first-generation PPI; RR 1.09, 95% CI 1.01 to 1.17 for high-dose versus standarddose PPIs). Several included studies did not provide information on the PPI used. Whether new-generation PPIs or high-dose PPIs should be used in all scenarios remains inconclusive; no evidence suggests that the treatment effect between durations differs between concomitant PPIs. In this systematic review, esomeprazole 20 mg bid was considered a standard-dose PPI and esomeprazole 40 mg bid was considered a high-dose PPI, because both the esomeprazole FDA label (Nexium 2012) and American Journal of Gastroenterology (AJG) guideline recommend esomeprazole be used 40 mg once daily (od) in H. pylori eradication (Chey 2007). Dose of PPI was included in the subgroup analysis when possible. Testing for subgroup differences was performed based on the fixedeffect inverse-variance method (implemented in RevMan) for H. pylori persistence. A P value less than 0.05 was chosen to define statistical heterogeneity in these analyses. With the PPI triple therapy, significant differences between all subgroups were only seen in 14 days versus seven days duration of treatment. We therefore tested further for subgroup differences by assessing the three nonquinolone subgroups, and then tested for the subgroup differences between PCA, PAN, and PCN. When we detected significant heterogeneity, we tried to explain it by the subgroup analyses detailed above.

Sensitivity analysis • We used reported eradication data with more relaxed ITT definitions (e.g., excluded patients who did not receive the medication, or excluded patients with negative second H. pylori

diagnostic test after randomisation) in the sensitivity analysis to see whether the conclusion changed compared to the strict ITT analysis. If it was not clear whether the reported ITT sample included all randomised participants, we excluded these studies from the sensitivity analysis. For studies that excluded patients who were lost to follow up from the ITT analysis, the eradication data with authors’ ITT definition was not considered in the sensitivity analysis because patients who were lost to follow up were considered as treatment failures in this review. • In some studies, metronidazole was used only for 10 days in the 14 days group due to “labelling reasons” (e.g., Dammann 2000). We excluded these studies from the sensitivity analysis. • We also excluded studies that had some uncertainties in the data (e.g., the time of H. pylori status assessment after treatment) from the sensitivity analysis. • A fixed-effect model was used. • If the RR was very close to one (pre-defined as any band of the 95% CI located within the range of 0.95 to 1.05 exclusively), we performed sensitivity analyses by using the fixed-effect model, by calculating OR, and using a desirable outcome (H. pylori eradicated) as the event to calculate the RR.

RESULTS

Description of studies See: Characteristics of included studies; Characteristics of excluded studies Results of the search In total, 1735 citations were identified; 1549 were excluded due to several reasons. The full texts of 186 citations were retrieved and reviewed (literature search outputs from major databases are shown in Figure 1). Of these, 110 were excluded due to various reasons. Seventy-five trials (76 citations) met our inclusion criteria and were included in the analyses. Characteristics of the included studies are listed in Characteristics of included studies.


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Figure 1. Study flow diagram.


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According to Cochrane Collaboration policy we performed an additional literature search in October 2013, prior to the publication of the review. We identified eight studies which may be eligible for inclusion in this review (Chen 2013; Choi 2012; Fallone 2013; Konorev 2012; Lv 2013; Prasertpetmanee 2013; Wang 2013; Xu 2012). These studies have not yet been assessed or included in our review. They will be systematically assessed and, if eligible they will be included in the next version of this review. Included studies Of the 75 eligible RCTs, eight types of regimens were reported with at least two comparative eligible durations. They included: 1. PPI + two antibiotics triple therapy (n = 59), 2. PPI bismuth-based quadruple therapy (n = 6), 3. PPI + three antibiotics quadruple therapy (n = 1), 4. PPI dual therapy (n = 2), 5. H2 RA bismuth-based quadruple therapy (n = 3), 6. H2 RA bismuth-based triple therapy (n = 2), 7. H2 RA + two antibiotics triple therapy (n = 3), and 8. bismuth + two antibiotics triple therapy (n = 2). Some studies provided data for more than one regimen or more than two duration comparisons. The sample size of included studies ranged from 20 (Grade 1996) to 909 (Zagari 2007). PPI triple therapy was the most reported regimen with 59 studies reporting five different antibiotic combinations, including clarithromycin plus amoxicillin (PCA), clarithromycin plus a nitroimidazole (PCN), amoxicillin plus a nitroimidazole (PAN), amoxicillin plus a quinolone (PAQ), and amoxicillin plus a nitrofuran (PANi). Some studies had more than one reported regimen (Characteristics of included studies). All three duration comparisons (14 versus 7 days, 10 versus 7 days, and 14 versus 10 days) were reported in the PCA and PAN regimens. PCN and PAQ had two durations (14 versus 7 days, 10 versus 7 days), and PANi had only one (10 versus 7 days) comparison reported. Forty-one per cent of the trials came from European countries (n = 31), including Italy (n = 18), Spain (n = 3), Netherlands (n = 2), Greece (n = 2), UK (n = 1), Germany (n = 1), Poland (n = 1), and Croatia (n = 3). Twenty-nine studies came from Asia, including mainland China and Taiwan and Hong Kong (n = 10), South Korea (n = 7), Turkey (n = 4), Iran (n = 3), Japan (n = 2), India (n = 2), and a multinational study from Thailand, China, Indonesia, the Philippines and Singapore. Seven studies came from North America: USA (n = 6), and Canada (n = 1). Six studies came from South America, including Argentina (n = 1), Brazil (n = 1), Chile (n = 1), Ecuador (n = 1), and Mexico (n = 2). Only two studies came from Africa, both of which were from South Africa. Four Turkish trials (Aydin 2007; Ercin 2010; Gumurdulu 2004; Simsek 1999) were analysed in the subgroup of Asian countries because the cities (Ankara, Izmir, and Adana) in which these trials were

located were on the Asian continent. Forty-six studies were singlecentre studies, eight studies were two-centre studies, and 20 were multicentre studies. One multinational study came from six Asian countries (Wong 2000) (Characteristics of included studies). All included study participants had H. pylori infection at enrolment. Twenty-nine studies included only patients with PUD (active or previously documented) at enrolment. Twenty four studies included patients with PUD as well as patients with FD or with mucosal inflammation (for example, gastritis, duodenitis, oesophagitis) or with normal endoscopy. Sixteen studies included patients with FD with or without mucosal inflammation, or dyspeptic patients without mucosal information. One study included patients with mucosal inflammation or patients with normal mucosa (Moayyedi 1996), and five studies only stated that they enrolled “patients withH. pylori infection” without further diagnostic information (Berrutti 2008; Knigge 1999; Laine 1996; Park 2009a; Simsek 1999). Seventeen studies reported primary (Antelo 2001; Aydin 2007; Bago 2010; Dammann 2000; Fennerty 1998; Filipec Kanizaj 2009; Garza González 2007; Hsu 2005; Hurenkamp 2000; Karatapanis 2011; Louw 1998b; Maconi 2001; Moayyedi 1996; Sun 2010; Vakil 2004; Wong 2000; Yang 1999) (n = 17) or acquired (n = 6) antibiotic resistance at baseline or after treatment (Dammann 2000; Fennerty 1998; Hsu 2005; Louw 1998b; Moayyedi 1996; Yang 1999) (Characteristics of included studies). All studies used H. pylori eradication as the primary outcome. Reported secondary outcomes varied, including mucosal inflammation; ulcer healing and factors related to ulcer healing; ulcer-related gastrointestinal symptom (for example, pain) resolution; ulcer recurrence; impact of antibiotic resistance on H. pylori eradication; other prognostic factors for H. pylori eradication rate or treatment failure; manifestation of follow-up esophagogastroduodenoscopy (EGD), etc (Characteristics of included studies).

Excluded studies One hundred and ten studies were excluded due to various reasons, including duplicate or preliminary data (n = 55), non-randomised trial (n = 19), ineligible regimens (n = 9) or ineligible durations (n = 1), ineligible H. pylori detecting method (n = 1), H. pylori eradication assessed less than four weeks after completion of antibiotics (n = 3), no ITT information (n = 3), no raw data for eradication rate (n = 7), solely a cost-effectiveness analysis (n = 2), a meta-analysis (n = 6), paediatric study (n = 1), suspicious data (n = 1), and those which we could not retrieve the full text or necessary information (n = 2) (Figure 1; Characteristics of excluded studies).

Risk of bias in included studies


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The methodological quality of the included studies is summarized in Characteristics of included studies, and shown in Figure 2. Only two studies (2.7%) were assessed as low risk of bias for all eight risk domains (Kim 2008; Zagari 2007); and 43 of 75 (57.3%) studies were assessed as at high risk of bias due to at least one of the risk domains being assessed as having a high risk of bias. Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Random sequence generation

Eleven out of 75 studies (14.7%) were considered high risk of bias for random sequence generation. A Chilean study was considered high risk because the randomisation was based on the last digit of the identification number: odd numbers were assigned to the seven-day group and even numbers were assigned to the 14-day group (Riquelme 2007). A Korean study assigned patients to the type of PPI “by lot”, then assigned patients to the one- or twoweek group by “date”. It was, therefore, a quasi-randomisation study, and the sample size was imbalanced between seven days and 14 days within the same PPI regimen (Keum 2005). One Chinese study, two Korean studies, two Japanese studies, one Italian study, and one Greek study were considered as high risk because no detailed information for randomisation method was provided and although terms such as “randomized” and “randomly” were used, sample size was substantially imbalanced between groups suggesting the likelihood that a genuine randomisation was not

performed (Ercin 2010; Hu 1999; Hu 2003; Kim 2007; Kiyota 1999; Lee 2004; Mantzaris 1999; Nakagawa 1999; Palmas 2002). Twenty-one studies were considered to have a low risk of bias for sequence generation as they provided information that proper randomisation was used. The remaining 43 studies were considered to have an unclear risk of bias for sequence generation because no detailed information was provided regarding the randomisation method.

Allocation concealment

Three out of 75 studies were considered to have a high risk of bias for allocation concealment. Two of the studies that were considered to have a high risk of bias for randomisation were also considered to have a high risk of bias for allocation concealment, because physicians could have predicted the next patient to be assigned to a particular group based on the date or the identification number (Keum 2005; Riquelme 2007). One Spanish study was considered to have a high risk of bias because the primary authors declared in the report that “concealment of allocation of the sequence of ran-


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domization was not performed” (Gisbert 2005a). Eleven studies were considered to have a low risk of bias for allocation concealment. All of these studies were also considered to have a low risk of bias for random sequence generation. The remaining 61 studies were considered to have an unclear risk of bias for allocation concealment because no detailed information was provided regarding the allocation concealment. Blinding

an open-label study usually refers to patients and physicians being not blinded. In addition, the assessment for H. pylori eradication is unlikely to have been impacted by the open-label design. Therefore, 54 studies were considered as unclear risk for detection bias and none of the studies were considered as high risk for detection bias.

Incomplete outcome data

Blinding of participants and personnel (performance bias)

H. pylori eradication

Among 75 studies, 30 (40.0%) were considered to have a high risk for performance bias (Bago 2010; Basu 2011; Berrutti 2008; Bosques-Padilla 2004; Calvet 2005a; Chaudhary 2004; Ching 1998; Dal Bo’ 1998; Di Caro 2002a; Di Mario 2003a; Dore 2011; Gisbert 2005a; Hsu 2005; Karatapanis 2011; Keum 2005; Kim 2007; Kiyota 1999; Maconi 2001; Mesquita 2005; Moayyedi 1996; Nakagawa 1999; Pozzato 1998; Riquelme 2007; Robles-Jara 2008; Sacco 2010; Savarino 1999; Scaccianoce 2006; Scaccianoce 2008; Sun 2010; Zheng 2009). All of these studies claimed that they were open-label studies, therefore no patients or physicians were blinded. An open-label study may lead to bias in adverse event reporting, different compliance, and medications out of the study regimens. Ten studies (13.3%) were considered to have a low risk of performance bias because they were of a double-blind design (Dammann 2000; Emami 2006; Fennerty 1998; Hurenkamp 2000; Kaviani 2001; Kim 2008; Lee 2004; Vakil 2004; Wong 2000; Zagari 2007). We considered double blind to refer to patients and physicians being blinded in most studies.

Most studies (52, 69.3%) were considered to have a low risk of bias for incomplete outcome data on H. pylori eradication. These studies either reported eradication in both the ITT and PP sample, or reported H. pylori eradication in the ITT sample and provided information on patients who were lost to follow up or dropped out. The proportion of patients with missing outcome data was balanced between groups with similar reasons for missing data across groups, making it unlikely to have had an impact on the treatment effect estimates. If a study reported eradication in the ITT sample only, and did not provide information regarding the patients lost to follow up or who dropped out, this study was considered to have an unclear risk of bias for the eradication data because it was not clear whether patients without outcome data were balanced between groups and whether it would have had an impact on the eradication effect estimate. If a study only reported eradication in the PP sample, we calculated the eradication rate based on the ITT sample by assuming all patients who were lost to follow up or dropped out had failed the eradication therapy, and we judged the risk of bias for incomplete outcome data based on whether the follow-up information was provided and was balanced between groups. If the proportion of patients missing outcomes was imbalanced between groups, without reasons given, we considered these studies to have a high risk of bias for incomplete outcome data on H. pylori eradication. In total, 17 studies (23.7%) were considered to have an unclear risk of bias for incomplete outcome data for H. pylori eradication. Six studies (8%) were considered to have a high risk of bias for incomplete H. pylori eradication outcome data. One Turkish study (Ercin 2010) reported eradication in the PP sample only, for which we calculated the eradication rate based on the ITT sample. The lost to follow-up rate was high (15%) because of the loss of contact with study participants. The loss of contact was imbalanced between the two groups (9/51 versus 3/40), with 18% from the 7 days group and 8% from the 14 days group. It was impossible to know the outcome of these patients so we presumed them all to have failed eradication, which can introduce bias. A study from Poland (Muszynki 1992) reported eradication data in the PP sample after excluding those who were lost to follow up and those who had discontinued treatment “due to intolerance”. We calculated the eradication rate by ITT, however the number of

Blinding of outcome assessment (detection bias)

Twenty-one studies (28%) were judged to have a low risk for detection bias. Fifteen studies reported that the outcome assessors were blinded to the treatment patients received, although some studies were open studies in which physicians and patients were unblinded (Bago 2010; Calvet 2005a; Dal Bo’ 1998; Dore 2011; Fennerty 1998; Filipec Kanizaj 2009; Gisbert 2005a; Hsu 2005; Hurenkamp 2000; Karatapanis 2011; Kaviani 2001; Kim 2008; Moayyedi 1996; Paoluzi 2006; Sun 2010). Six doubleblind studies did not directly report that outcome assessors were blinded (Dammann 2000; Emami 2006; Lee 2004; Vakil 2004; Wong 2000; Zagari 2007). However, considering the nature of the double-blind design, outcome assessors for H. pylori eradication (for example. laboratory technicians, pathologists, microbiologists) were blinded in studies that tried to keep patients and physicians blinded. Therefore, these studies were considered as low risk for detection bias. As for some open-label studies that did not provide blinding information for outcome assessors, we considered it unclear whether the outcome assessors for H. pylori eradication were aware of the treatment patients received, because


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participants lost to follow up was imbalanced (4 versus 1), which can have impact on the treatment effect estimate. In an Italian study (Paoluzi 2006), eradication was reported in the ITT and PP samples. Seventy-five (15%) of the patients dropped out and there was an imbalance between the groups (10% versus 21%). Some between-group eradication rate difference was seen in the ITT analysis but not in the PP analysis. Reasons for exclusion in the PP sample were provided for patients overall but not separately for the groups. In a Chilean study (Riquelme 2007), eradication was reported in the ITT and the PP samples. Patient numbers were provided for those who were lost to follow up or who discontinued treatment due to adverse events. However, there were more patients lost to follow up in the 7 days group than the 14 days group (6 versus 2). It was unclear whether the imbalanced withdrawal had an impact on the treatment effect estimate. In an Ecuadorian study (Robles-Jara 2008), eradication was reported in the authors’ defined ITT and PP analyses. The authors excluded nine patients who were lost to follow up in their ITT analysis, which was imbalanced between the 10 days (n = 6) and 7 days groups (n = 3). We used all randomised patients as the ITT sample size and presumed that those lost to follow up had failed H. pylori eradication. However, the imbalanced losses to follow up (9% versus 4%) might have impacted on the treatment effect estimate. In a study from Taiwan (Yang 1999), eradication data were reported for the PP sample. We calculated eradication in the ITT sample. Dropouts were higher in the 7 days group (18%) than in the 14 days group (12%). The imbalance of patients who had no outcome data might have impacted on the treatment effect estimate.

Adverse events

Study participants who were lost to follow up or who dropped out could be the result of adverse events, so the imbalance of dropouts has more impact on the adverse event outcome analyses than the H. pylori eradication efficacy analyses between groups. Reporting adverse events in the ITT sample or the PP sample only might lead to an underestimate or overestimate of the adverse event rate depending on the reasons for excluding patients from the PP analysis. For studies that did not report data for adverse events, they were considered to have an unclear risk of bias; although these studies might not have planned to report this outcome. These studies did not contribute to our analyses for adverse events. For studies that reported adverse events in the ITT sample only but did not report details of dropouts, especially how many patients discontinued treatment due to adverse events in the eligible groups, they were considered to have an unclear risk of bias because it was not clear what the impact of dropping out would have been on the adverse events analyses. For studies that reported adverse events only in event numbers, it was not known how many patients had an adverse event, and how many patients contributed to the adverse event analysis, therefore the data were not analysable and these studies were considered to have an unclear risk of bias as well.

Some studies provided details for patients with adverse events, and provided the data of patients who were lost to follow up or dropped out. Although we did not know the adverse event outcomes for these patients, if the reason for dropping out was provided and was not adverse event-related, or if the numbers lost to follow up and dropping out were balanced between the groups, we considered that the participants lost to follow up or who had dropped out were less likely to have been related to the outcome adverse events analyses, and we therefore considered these studies to have a low risk of bias. If patients without outcome data were substantially imbalanced in the groups, these studies were considered to have a high risk of bias for incomplete data for adverse events. Thirtynine studies (52.0%) were considered to have an unclear risk of bias and 30 studies (40.0%) were considered to have a low risk of bias for incomplete outcome data for adverse events. In total, six studies (8%) were considered to have a high risk of bias for incomplete outcome data for adverse events. A Turkish study (Ercin 2010) only reported adverse events that caused treatment to be stopped (n = 2). The author responded to our enquiry, that “all completed study except the 9+3 patients lost to follow up, all other patients had no adverse events”. However, the loss of contact was imbalanced between the two groups (9/51 versus 3/40). In a Greek conference proceeding (Mantzaris 1999), it was unclear whether the analysis for adverse events was based on the PP sample as the percentage did not match the provided patient numbers and PP sample size. In a Polish study (Muszynki 1992), adverse events were reported in patients except those lost to follow up. It was unclear whether any of those lost to follow up discontinued treatment due to adverse events. The patients lost to follow up were imbalanced (4 versus 1). In an Italian study (Paoluzi 2006), adverse events were reported after excluding patients lost to follow up. They reported 32 patients lost to follow up and 23 patients who withdrew due to adverse events, without separately reporting data for the treatment groups. However, adverse events were combined for the one week and two weeks groups. Therefore, no analysis was possible for comparing one and two weeks. In a Chilean study (Riquelme 2007), adverse events were reported in the ITT sample, where individual adverse events were reported. There were more patients lost to follow up in the seven days group (6 versus 2), and this might have had an impact on the adverse events analysis. In a study from Taiwan (Yang 1999), symptoms of adverse events were not recorded in the patients in one hospital. Therefore, adverse events were only available for 239 out of 297 patients, and the analysed sample size was not provided for each group. We could only use the PP sample in the analysis. Therefore, 20% of patients had missing outcome data, which might have impacted on the adverse event analysis.

Selective reporting All studies reported H. pylori eradication as the primary outcome. Therefore, the reporting bias was considered for adverse events as


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the secondary outcome. Studies reporting adverse events in patients overall, without raw data for each group, were considered to have a high risk of bias for selective reporting. When authors planned to record adverse events, then adverse events were expected to be reported for all treatment groups as an important outcome. If a conference proceeding did not report adverse events data, we considered it to have an unclear risk of reporting bias for adverse events, because it was not clear whether the adverse event reporting was a planned outcome. If a study did not report a planned outcome but it was not our outcome of interest, we also considered it to have an unclear risk of reporting bias to avoid an impact on our overall risk of bias assessment. In total, 12 studies (16%) were considered to have an unclear risk for reporting bias. Ten studies (13%) were considered to have a high risk of bias for reporting adverse events. A study from the US (Basu 2011) reported adverse events and discontinued treatment, but the results were combined for both groups; the combined analysis was not planned. A Chinese study (Cui 2002) reported adverse events as the total for pantoprazole or omeprazole patients. It was not clear how many patients had adverse events in each duration group. A German study (Dammann 2000) reported patients who discontinued treatment due to adverse events, however the number of patients in each group was not known. A Chinese study (Hu 2003) reported adverse events in the mixed H2 RA-based groups and the mixed PPI-based groups as the percentage only. Adverse events were reported within the same PPI regimens but were not separated for the one-week or two-week arms in a Korean study (Keum 2005). In a US study (Knigge 1999), individual adverse events were reported but the data were combined for the two groups. In an Italian study (Paoluzi 2006), adverse events were reported after excluding patients lost to follow up. However, events were combined for the one-week and two-week groups, separated for the omeprazole, amoxicillin, clarithromycin (OAC) and omeprazole, metronidazole, clarithromycin (OMC) groups. Twenty-three patients withdrew due to adverse events but the data were combined for all groups. In another Italian study (Pellicano 2002), adverse events were only reported as: “frequency of adverse events were evenly distributed between the groups”. A third Italian study (Palmas 2002) did not report adverse events except to state “side effects infrequent and mild”; duodenal ulcer (DU) recurrence was recorded but no outcome data were reported. In an Ecuadorian study (Robles-Jara 2008), adverse events attributed to non-compliance were reported for the 10 days group in the ITT sample. The authors did not report whether any adverse events were reported in the seven days group.

(Yuan 2012). In an Italian study (Dore 2011), the primary authors reported (in table 5) patients with adverse events as 32 versus 22 in the 14 days versus 10 days groups. However, the number of patients with unfitness or discomfort was 40 versus 18, and fatigue or weakness 32 versus 20. We confirmed with the primary authors that some patients reported adverse events that were judged as not drug-related and were not considered as side effects. It was unclear how the primary authors decided which patients who reported adverse events did have adverse events. In an Italian study (Scaccianoce 2008), the study stopped after half of the patients were enrolled due to a data-dependent process (the low eradication rate in the interim analysis). The early stopping of the trial might have introduced bias. Thirteen studies were considered to have an unclear risk for other potential sources of bias. In an Italian study (Berrutti 2008), the authors stated in the methods that they excluded patients from the ITT and PP analysis with poor compliance, unknown posttreatment H. pylori status, or protocol deviations. Finally, all three excluded patients were those who discontinued treatment due to adverse events. It was unclear whether the exclusion criteria were planned before the study. In another Italian study (Suriani 2008), preliminary data of 49 patients out of 61 were reported in a conference proceeding. However, information for the other patients wasn’t available until we updated the search. In another Italian study (Sacco 2008), according to the conference abstract patients were randomised to three arms, but the full paper (Sacco 2010) reported it as four arms. It was not clear whether the fourth group was added or just not reported in the abstract. Ten conference proceedings were also considered to have an unclear risk of other potential sources of bias, because there was insufficient information to assess whether an important risk of bias existed (Grade 1996; Kang 2000a; Katicic 1997; Lee 2004; Lv 2011; Mantzaris 1999; Mones 1997; Paoluzi 1998; Park 2009a; Simsek 1999).

Effects of interventions See: Summary of findings for the main comparison PPI triple therapy for 14 days versus 7 days for Helicobacter pylori eradication; Summary of findings 2 PPI triple therapy for 10 days versus 7 days for Helicobacter pylori eradication; Summary of findings 3 PPI triple therapy for 14 days versus 10 days for Helicobacter pylori eradication Efficacy analysis See: Summary of findings for the main comparison; Summary of findings 2; Summary of findings 3

Other potential sources of bias Three studies were considered to have a high risk for other potential sources of bias. In a US study (Basu 2011), some inconsistencies between the full publication and the published abstracts were found, especially for the time of the H. pylori eradication test

1. PPI triple therapy

Of the PPI triple therapy, 59 studies (n = 14,461) with four types of regimens were reported: PPI + clarithromycin + amoxicillin (PCA); PPI + clarithromycin + a nitroimidazole (PCN); PPI +


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amoxicillin + a nitroimidazole (PAN); and PPI + amoxicillin + a quinolone (PAQ). H. pylori eradication was compared for 14 days versus 7 days, 10 days versus 7 days, and 14 versus 10 days, respectively (Analysis 1.1; Analysis 2.1; Analysis 3.1). 1.1. PPI triple therapy 14 days versus 7 days In total, 45 studies with 50 comparisons were analysed in four different regimen subgroups. Five studies provided more than one comparison under different subgroups (Filipec Kanizaj 2009; Hu 2004; Katicic 1997; Paoluzi 1998; Paoluzi 2006). Three studies provided more than one comparison under the same subgroup: using different doses of antibiotics, different types of PPI, or different antibiotics within the same class (Berrutti 2008; Hu 2004; Keum 2005). We combined data for the same PPI triple regimen subgroup. Regardless of the type and dose of antibiotics, increased duration of PPI triple therapy (from 7 to 14 days) significantly increased the H. pylori eradication rate (72.9% versus 81.9%), RR for H. pylori persistence was 0.66 (95% CI 0.60 to 0.74), NNT was 11 (95% CI 9 to 14), with moderate heterogeneity (Chi² test P = 0.03, I² = 30%) (Analysis 1.1).

Significant differences between four regimen subgroups were seen (P = 0.02). We therefore further tested for subgroup differences by assessing the three non-quinolone subgroups: the subgroup differences of three regimens were reduced (P = 0.12). We further tested for subgroup differences between PCA, PCN, and PAN. Marginal significant subgroup differences were seen between PCA and PCN (P = 0.05), but not for PCA versus PAN (P = 0.84) nor for PCN versus PAN (P = 0.10). The assessment and results of the funnel plot asymmetry indicated that publication bias or other small study effects may be present for the outcome of H. pylori persistence in the comparison of all PPI triple therapy 14 days vs 7 days (Figure 3). When 50 comparisons were separated by regimens in the analysis, for Begg-Mazumdar’s test the Kendall’s tau = -0.26, P = 0.007; for Egger’s test bias = -1.15 (95% CI -1.81 to -0.49), P = 0.001; for Horbold-Egger test the bias = -0.99 (92.5% CI -1.71 to -0.27), P = 0.02. When the data from different regimens were combined for the same study (45 studies, 45 comparisons), for Begg-Mazumdar’s test the Kendall’s tau = -0.22, P = 0.003; for Egger’s test bias = -1.09 (95% CI 1.82 to -0.36), P = 0.005; for Horbold-Egger test the bias = -0.91 (92.5% CI -1.69 to -0.13), P = 0.04.

Figure 3. Funnel plot of comparison: 1 PPI + two antibiotics triple therapy, 14 days versus 7 days, main analyses, outcome: 1.1 H. pylori persistence, subgroup by antibiotics regimens, regardless of dose.


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Subgroup analyses by baseline PUD or FD 1.1.1. PCA triple therapy, 14 versus 7 days Thirty-four studies (n = 5801) compared H. pylori eradication rate with PCA triple therapy for 14 days with 7 days. The eradication rate was significantly increased from 7 days (74.9%) to 14 days (83.5%), with a RR for H. pylori persistence of 0.65 (95% CI 0.57 to 0.75). Moderate but significant heterogeneity was seen between studies (P = 0.05, I² = 30%) (Figure 3); NNT was 12 (95% CI 9 to 16) (Analysis 1.1).

Subgroup analysis

Subgroup analyses by regimens Effect estimates for four dose subgroups were performed (Analysis 4.1). For PPI and antibiotics used bid at a standard dose (28 studies, n = 5103), RR for H. pylori persistence was 0.66 (95% CI 0.59 to 0.75), NNT was 12 (95% CI 10 to 16) with no statistical heterogeneity between studies (P = 0.20, I² = 18%) (Analysis 4.1.1). For PPI standard dose used once daily or a low dose twice daily, and two antibiotics used at standard dose twice daily (3 studies, n = 198), the RR was 0.80 (95% CI 0.20 to 3.29) with significant heterogeneity between studies (P = 0.02, I² = 74%) (Analysis 4.1.2). The RR for PPI and amoxicillin used at standard dose twice daily but clarithromycin used at a low dose (2 studies, n = 236) was 0.59 (95% CI 0.32 to 1.09) without heterogeneity between studies (P = 0.68, I² = 0%) (Analysis 4.1.3). For studies of PPI used once daily, clarithromycin and amoxicillin both used at a low dose (3 studies, n = 264), RR was 0.52 (95% CI 0.22 to 1.24) with significant heterogeneity (P = 0.07, I² = 63%) (Analysis 4.1.4). No significant difference was seen between the subgroups (P = 0.68, I² = 0%). A study that did not clearly state the type and dose of PPI used (Park 2009a) was placed into the standard dose subgroup to avoid too many subgroups in this analysis. Subgroup analyses by geographic location Subgroup analysis of geographic regions (Analysis 4.2) showed that RR for H. pylori persistence was 0.63 (95% CI 0.52 to 0.75), 0.66 (95% CI 0.54 to 0.82), 1.06 (95% CI 0.51 to 2.19), and 0.39 (95% CI 0.15 to 1.03) for Asian countries (15 studies, n = 3167), European countries (13 studies, n = 2135), South or North American countries (4 studies, n = 370), and South Africa (2 studies, n = 129), respectively. Tests for heterogeneity showed moderately significant heterogeneity (P = 0.07, I² = 38%) (Analysis 4.2.1), no significant heterogeneity (P = 0.22, I² = 22%) (Analysis 4.2.2), moderate heterogeneity (P = 0.11, I² = 51%) (Analysis 4.2.3), and no significant heterogeneity (P = 0.88, I² = 0%) (Analysis 4.2.4), respectively. The NNT was 10 (95% CI 8 to 15) and 12 (95% CI 9 to 22) for Asian and European countries, respectively. No statistically significant subgroup difference was seen between the four regions (P = 0.15).

Within the 34 studies in this PCA 14 versus 7 days group, 22 studies (14 comparisons) enrolled patients with PUD only or FD only, or provided data for the subgroups of PUD and FD (Analysis 4.3). Two studies provided raw data of H. pylori eradication rates for patients with PUD and non-PUD for 14 versus 7 days (Maconi 2001; Riquelme 2007). For patients with PUD (18 studies, n = 3823), the eradication rate was significantly increased in the 14 days group (83.1% versus 76.1%), with a RR for H. pylori persistence of 0.72 (95% CI 0.63 to 0.83) and NNT = 15 (95% CI 11 to 24) with no significant heterogeneity between studies (P = 0.35, I² = 9%) (Analysis 4.3.1). For patients with FD (6 studies, n = 411), a non-significant increase in eradication rate was seen with the 14 days duration (82.1% versus 74.9%), with RR = 0.70 (95% CI 0.39 to 1.26) and statistically significant heterogeneity (P = 0.07, I² = 51%) (Analysis 4.3.2). No significant subgroup difference was seen between the two subgroups (P = 0.74, I² = 0%) (Analysis 4.3.2). For the remaining studies that mixed participants with and without PUD, or without specifying the type of baseline disease, the eradication rate was significantly increased in the 14 days group (12 studies, n = 1567), with RR = 0.57 (95% CI 0.44 to 0.73), NNT = 8 (95% CI 6 to 13) and mild heterogeneity between studies (I² = 27%) but this was of borderline statistical significance (P = 0.18) (Analysis 4.3). No statistically significant subgroup difference was seen between the three subgroups (P = 0.14, I² = 49.8%).

Subgroup analyses by risk of bias: allocation concealment With the 34 studies in this group, only three were judged to have a low risk of bias for allocation concealment (Filipec Kanizaj 2009; Kim 2008; Zagari 2007). Two were judged to have a high risk of bias for allocation concealment (Keum 2005; Riquelme 2007) (Analysis 4.4). No significant difference in the H. pylori persistence rate was detected between 14 days and 7 days only for the three low risk studies (n = 1010) that had adequate allocation concealment (RR for H. pylori persistence of 0.69, 95% CI 0.37 to 1.26, test for heterogeneity P = 0.04, I² = 69%). For the other two studies (n = 483) with inadequate allocation concealment, a significant difference in eradication rate was seen between 14 days and 7 days (88.3% versus 76.2%), with RR for H. pylori persistence of 0.50 (95% CI 0.33 to 0.74), NNT = 8 (95% CI 6 to 16) with no significant heterogeneity between studies (P = 0.36, I² = 0%). For the remaining 29 studies with an unclear risk of bias for allocation concealment (n = 4308), a significant difference in eradication rate was seen between 14 days and 7 days (83.0% versus 73.9%), with a RR for H. pylori persistence of 0.66 (95% CI 0.57 to 0.76), NNT = 12 (95% CI 9 to 16), with no significant heterogeneity between studies (P = 0.15, I² = 22%). No statistically significant subgroup difference was seen between the three subgroups (P = 0.11).


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Subgroup analyses by risk of bias: overall

1.1.2. PCN triple therapy, 14 versus 7 days

When all risk domains were considered within the 34 studies in this group, only two of them were judged to have a low risk of bias (Kim 2008; Zagari 2007); 14 were considered to have a high risk of bias and 18 were considered to have an unclear risk of bias (Analysis 4.5). There was no significant difference for H. pylori persistence rate between the 14 days and 7 days durations for the two low risk studies (n = 833) that had adequate allocation concealment (RR for H. pylori persistence 0.89, 95% CI 0.68 to 1.16). For the 14 high risk studies (n = 3081), a significant difference in eradication rate was seen between 14 days and 7 days (83.2% versus 74.5%), with RR for H. pylori persistence = 0.68 (95% CI 0.60 to 0.79), NNT = 12 (95% CI 10 to 18) and no significant heterogeneity between studies (P = 0.49, I² = 0%). For the 18 studies with unclear risk of bias (n = 1887), a significant difference in eradication rate was seen between 14 days and 7 days (85.0% versus 73.9%), with a RR for H. pylori persistence of 0.56 (95% CI 0.42 to 0.75), NNT = 9 (95% CI 7 to 15), with significant heterogeneity between studies (P = 0.01, I² = 47%). No statistically significant subgroup difference was seen between the three subgroups (P = 0.12).

Four studies (n = 688) compared H. pylori eradication rate with PCN triple therapy for 14 days versus 7 days (Dal Bo’ 1998; Dammann 2000; Paoluzi 1998; Paoluzi 2006). The only nitroimidazole used was metronidazole in all studies. Two studies used standard dose metronidazole 500 mg bid (Paoluzi 1998; Paoluzi 2006); one study used metronidazole for only 10 days in the 14 days group due to “labelling reasons” (Dammann 2000); and one study used low-dose clarithromycin (250 mg bid) and metronidazole 250 mg qid (Dal Bo’ 1998). We combined data for lansoprazole + clarithromycin + metronidazole with omeprazole + clarithromycin + metronidazole for one study (Paoluzi 1998). The eradication rate was not significantly different between 7 days (64.2%) and 14 days (68.6%), RR for H. pylori persistence of 0.87 (95% CI 0.71 to 1.07), and no significant heterogeneity was seen between studies (P = 0.72, I² = 0%) (Analysis 1.1).

Sensitivity analyses Four studies from this group were excluded in the sensitivity analysis as discussed above (Cho 2001; Gumurdulu 2004; Kang 2000a; Kiyota 1999). A significantly increased H. pylori eradication rate was shown with 14 versus 7 days (83.6% versus 75.8%, n = 5102), RR for H. pylori persistence of 0.68 (95% CI 0.59 to 0.78), NNT = 13 (95% CI 10 to 19), with no significant heterogeneity between studies (P = 0.14, I² = 23%). If the eradication data from the authors’ ITT definition were used instead of our strict ITT definition, in five studies (Antelo 2001; Aydin 2007; Louw 1998a; Moayyedi 1996; Zagari 2007), similar effect estimates were seen between the 14 versus 7 days groups, either in the analysis of all studies (n = 5783, H. pylori eradication rate 83.6% versus 75.2%; RR 0.66, 95% CI 0.57 to 0.75; NNT = 12, 95% CI 9 to 16; test for heterogeneity P = 0.05, I² = 30%), or in the sensitivity analysis after excluding four RCTs (n = 5084, H. pylori eradication rate 83.8% versus 76.1%; RR for H. pylori persistence 0.68, 95% CI 0.59 to 0.78; NNT = 13, 95% CI 10 to 19; test for heterogeneity P = 0.14, I² = 22%).

Subgroup analyses Subgroup analyses by regimens No significant difference between 14 and 7 days was seen in studies using standard dose PPI and antibiotics (RR 0.85, 95% CI 0.66 to 1.12, n = 2), the study using 10 days of metronidazole in the 14 days group (RR 0.95, 95% CI 0.62 to 1.46, n = 1) or in the study using low-dose clarithromycin (RR 0.76, 95% CI 0.38 to 1.53, n = 1) (Analysis 7.1). No significant subgroup difference was seen (P = 0.85). Subgroup analyses by geographic location All studies came from Italy except one German study (Dammann 2000). No subgroup analysis was performed for regions (Analysis 7.2). Subgroup analyses by baseline PUD or FD Four studies in this group included patients with different baseline diseases; with FD only (Dal Bo’ 1998; Paoluzi 1998), DU only (Dammann 2000), and both patients with FD or PUD (Paoluzi 2006) (Analysis 7.3). No significant difference for H. pylori eradication was seen for all subgroups, with a RR for H. pylori persistence of 0.95 (95% 0.62 to 1.46), 0.69 (95% CI 0.42 to 1.11), and 0.91 (95% CI 0.69 to 1.19), respectively.

Publication bias and other small study effects The assessment of the funnel plot asymmetry and results of the Egger tests indicated that publication bias or other small study effects may be present for the outcome H. pylori persistence in the comparison of 14 versus 7 days. For Begg-Mazumdar’s test, Kendall’s tau = -0.23, P = 0.057; for Egger’s test bias = -1 (95% CI -1.79 to -0.2), P = 0.016; for Horbold-Egger test, bias = -0.92 (92.5% CI -1.78 to -0.06), P = 0.059.

Subgroup analyses by risk of bias No study in this group was judged to have appropriate or inappropriate allocation concealment; therefore no subgroup analysis for allocation concealment was performed. When all risk domains were considered, of the three studies only one was considered to have an unclear risk of bias (Paoluzi 1998). No study was considered to have a low risk of bias and the remaining three studies were


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considered to have a high risk of bias (Dal Bo’ 1998; Dammann 2000; Paoluzi 2006). No significant difference between 14 days and 7 days was seen for both subgroups, with RR for H. pylori persistence of 0.63 (95% CI 0.32 to 1.22) and 0.90 (95% CI 0.73 to 1.12) for the unclear risk and high risk subgroup, respectively (Analysis 7.4). No statistically significant subgroup difference was seen between the three subgroups (P = 0.31).

Sensitivity analyses One study was excluded in the sensitivity analysis because metronidazole was used only for 10 days in the 14 days group, as discussed (Dammann 2000). A similar result was found with this study excluded (RR 0.85, 95% CI 0.67 to 1.07).

Publication bias and other small study effects Only four studies were included in this regimen for 14 days versus 7 days, therefore neither a funnel plot nor test for funnel plot asymmetry were performed.

1.1.3. PAN triple therapy, 14 versus 7 days Ten studies (n =1066) compared H. pylori eradication rate with PAN triple therapy for 14 days with 7 days. The nitroimidazole used was metronidazole 400 mg bid in four studies (Cui 2002; Hu 1999; Hu 2003; Hu 2004), metronidazole 500 mg bid in four studies (Filipec Kanizaj 2009; Katicic 1997; Pellicano 2002; Wong 2000), metronidazole 250 mg qid in one study (Berrutti 2008), and tinidazole 500 mg bid in two studies (Berrutti 2008; Chaudhary 2004). PPIs and amoxicillin were used as a standard dose bid in all studies. H. pylori eradication rate was significantly increased from 7 days (72.7%) to 14 days (82.0%), with a RR for H. pylori persistence of 0.67 (95% CI 0.52 to 0.86, P = 0.001), an NNT of 11 (95% CI 8 to 25); no significant heterogeneity was seen between studies (P = 0.38, I² = 7%) (Analysis 1.1).

Subgroup analyses by geographic location Six studies were from Asia and four were from European countries. Subgroup analysis of the geographic regions showed that the RR for H. pylori persistence was 0.63 (95% CI 0.45 to 0.89; NNT 11, 95% CI 7 to 36) and 0.68 (95% CI 0.41 to 1.13) for Asian and European countries, respectively. Tests for heterogeneity showed no significant heterogeneity (P = 0.67, I² = 0%) and moderate heterogeneity (P = 0.08, I² = 57%), respectively. There was no statistically significant heterogeneity between the two regions (P = 0.63) (Analysis 9.2). Subgroup analyses by baseline PUD or FD With the 10 studies of this group, five studies enrolled patients with PUD only (Chaudhary 2004; Hu 1999; Hu 2004; Pellicano 2002; Wong 2000), one enrolled patients with symptomatic gastritis (Cui 2002), and four had mixed patients with PUD and FD or did not provide detailed information for the baseline disease ( Berrutti 2008; Filipec Kanizaj 2009; Hu 2003; Katicic 1997). For the five studies with PUD patients only, the eradication rate was significantly increased in the 14 days group (70.5% versus 80.8%), RR for H. pylori persistence of 0.67 (95% CI 0.47 to 0.94), NNT = 10 (95% CI 6 to 60), and no significant heterogeneity between studies (P = 0.42, I² = 0%). For the four studies that mixed patients with and without PUD, the eradication rate was not significantly different between 7 and 14 days, with a RR for H. pylori persistence of 0.63 (95% CI 0.38 to 1.04) (test for heterogeneity P = 0.14, I² = 46%). The 95% CI was very close to one, therefore a sensitivity analysis was performed for this subgroup. The RR for H. pylori persistence was 0.59 (95% CI 0.42 to 0.85, P = 0.004) using a fixed-effect model. Using a random-effects model, the odds ratio (OR) was 0.52 (95% CI 0.27 to 1.00, P = 0.05). If using H. pylori eradication as the outcome, the RR was 1.16 (95% CI 1.03 to 1.12, P = 0.02). For the only study that included FD patients only, the RR was 0.85 (95% CI 0.38 to 1.93). No significant subgroup difference was seen (P = 0.59) (Analysis 9.3).

Subgroup analyses Subgroup analyses by risk of bias: allocation concealment Subgroup analysis by regimen The significant difference between 14 and 7 days disappeared when the analysis was broken down to subgroups according to the type and dose of nitroimidazole, although there was still a trend in favour of the 14 days group in the three subgroups. RR for H. pylori persistence was 0.64 (95% CI 0.41 to 1.01, P = 0.06), 0.64 (95% CI 0.40 to 1.01, P = 0.05), 1.13 (95% CI 0.48 to 1.01, P = 0.77), and 0.57 (95% CI 0.26 to 1.27, P = 0.17) for the subgroups using metronidazole 400 mg bid (n = 4), metronidazole 500 mg bid (n = 4), metronidazole 250 mg qid (n = 1), and tinidazole 500 mg bid (n = 2), respectively (Analysis 9.1). No significant subgroup difference was found (P = 0.64).

All studies were judged as having unclear allocation concealment except two, which were considered as low risk (Berrutti 2008; Filipec Kanizaj 2009). No significant difference was seen for H. pylori persistence in the two studies with low risk (RR 0.54, 95% CI 0.14 to 2.11). For studies with unclear risk of bias for allocation concealment, the H. pylori eradication rate was significantly increased with 14 days duration (81.3% versus 71.9%), RR for H. pylori persistence of 0.67 (95% CI 0.51 to 0.87), NNT = 11 (95% CI 7 to 28). No significant subgroup differences were seen (P = 0.96) (Analysis 9.4). Subgroup analyses by risk of bias: overall


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When all risk domains were considered, six studies were assessed to have a high risk of bias and four were assessed to have an unclear risk of bias. No significant difference was seen for H. pylori persistence in the six high risk studies, with a RR of 0.81 (95% CI 0.58 to 1.12) (test for heterogeneity P = 0.61, I² = 0%). For the four studies with unclear risk of bias, the H. pylori eradication rate was significantly increased with 14 days duration (82.7% versus 70.4 %), RR for H. pylori persistence of 0.54 (95% CI 0.37 to 0.78), NNT = 7 (95% CI 5 to 16) (test for heterogeneity P = 0.33, I² = 12%). No significant subgroup difference was seen (P = 0.10) (Analysis 9.5).

Sensitivity analysis One study was excluded in the sensitivity analysis because metronidazole was used for only 10 days in the 14 days group (Katicic 1997). The other study was excluded due to questionable randomisation (Hu 2003) (Characteristics of included studies). A significant difference between 14 days versus 7 days was still shown with a RR for H. pylori persistence of 0.67 (95% CI 0.48 to 0.92), NNT = 12 (95% CI 8to 49), with no significant heterogeneity between studies (P = 0.23, I² = 0%).

Publication bias and other small study effects The overview of the funnel plot and results of the tests for funnel plot asymmetry indicated that there was no evidence of publication bias or other small study effects for the outcome of H. pylori persistence in the comparison of 14 versus 7 days PAN triple therapy. Begg-Mazumdar test Kendall’s tau = -0.42, P = 0.07; Egger’s test bias = -1.95 (95% CI -5.01 to 1.1), P = 0.18; for HorboldEgger test, bias = -0.1 (92.5% CI -3.43 to 3.22), P = 0.95. 1.1.4. PAQ triple therapy, 14 versus 7 days Two studies compared the H. pylori eradication rate of PAQ triple therapy for 14 versus 7 days (Bosques-Padilla 2004; Ercin 2010). One was a Mexican multicentre RCT with 76 patients with dyspeptic symptoms and H. pylori infection but two were DU pa-

tients (Bosques-Padilla 2004). The PPI triple regimen used was rabeprazole 20 mg bid, ofloxacin 400 mg bid, and amoxicillin 1 g bid. The second study was a Turkish study of 91 FD patients (Ercin 2010). The PPI triple regimen used was lansoprazole 30 mg bid, amoxicillin 1 g bid, and levofloxacin 500 mg od. The H. pylori eradication rate was significantly increased with 14 days duration (78.5% versus 42.0 %), with a RR forH. pylori persistence of 0.37 (95% CI 0.16 to 0.83), NNT= 3 (95% CI 2 to 10) (Analysis 12.1). Both studies had an unclear risk for allocation concealment, but one study was considered to have a high risk for randomisation and incomplete outcome data (Ercin 2010) and one study had a high risk for blinding of participants and personnel (Bosques-Padilla 2004). No sensitivity analysis was necessary. It was not possible to assess funnel plot asymmetry as only two studies were available for this subgroup. 1.2. PPI triple therapy 10 days versus 7 days In total, 24 studies with 26 comparisons are analysed under five different regimen subgroups. Two studies (Filipec Kanizaj 2009; Katicic 1997) provided more than one comparison under different subgroups. One study (Berrutti 2008) provided more than one comparison under the same subgroup (PPI + amoxicillin + a nitroimidazole) that used different nitroimidazoles (metronidazole and tinidazole). We combined data for the same PPI triple regimen subgroup. Regardless of the type and dose of antibiotics, increased duration of PPI triple therapy from 7 to 10 days significantly increased the H. pylori eradication rate (75.7% versus 79.9%), RR for H. pylori persistence was 0.80 (95% CI 0.72 to 0.89), NNT = 21 (95% CI 15 to 38), without significant heterogeneity (test for heterogeneity P = 1.00, I² = 0%) (Analysis 2.1). The overview of the funnel plot and results of the tests for funnel plot asymmetry indicated that there was no evidence for publication bias or other small study effects for PPI triple therapy 10 versus 7 days. Begg-Mazumdar test Kendall’s tau = -0.13, P = 0.34; for Egger’s test bias = -0.32 (95% CI -0.96 to 0.31), P = 0.30; for Horbold-Egger test, bias = -0.28 (92.5% CI -0.85 to 0.30), P = 0.38 (Figure 4).


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Figure 4. Funnel plot of comparison: 2 PPI + two antibiotics triple therapy, 10 days versus 7 days, main analyses, outcome: 2.1 H. pylori persistence, subgroup by antibiotics regimens, regardless of dose.

No significant subgroup differences were seen (P = 0.67). 1.2.1. PCA triple therapy, 10 versus 7 days Seventeen studies (n = 3271) compared H. pylori eradication rate with PCA triple therapy for 10 days with 7 days. The eradication rate was significantly increased from 7 days (76.2%) to 10 days (80.5%), with RR for H. pylori persistence of 0.80 (95% CI 0.70 to 0.91). No significant heterogeneity was seen between studies (P = 1.00, I² = 0%). The NNT was 21 (95% CI 14 to 48) (Analysis 2.1).

Subgroup analysis

Subgroup analyses by regimen Fifteen of the 17 studies used a standard dose of PPI and antibiotics bid. However, one study did not provide detail on the type and dose of PPI used (Park 2009a) and one study used high dose PPI (esomeprazole 40 mg bid) (Gisbert 2005a). In the subgroup of standard dose PPI and antibiotics, the eradication rate was significantly increased from 7 days (76.1%) to 10 days (80.0%), with

RR for H. pylori persistence of 0.79 (95% CI 0.69 to 0.91). No significant heterogeneity was seen between studies (P = 1.00, I² = 0%). The NNT was 20 (95% CI 14 to 47) (Analysis 5.1).

Subgroup analyses by geographic location Four studies were from Asia, nine from European countries, three from the US and one from South America. Subgroup analysis of geographic regions (Analysis 5.2) showed that the RR for H. pylori persistence was 0.79 (95% CI 0.57 to 1.11), 0.78 (95% CI 0.66 to 0.92), and 0.86 (95% CI 0.65 to 1.13), for Asian countries (4 studies, n = 655), European countries (9 studies, n = 1958), and South or North American countries (4 studies, n = 650), respectively. Tests for heterogeneity showed no significant heterogeneity for all three subgroups (P = 0.97, I² = 0% (Analysis 5.2.1); P = 1.00, I² = 0% (Analysis 5.2.2); and P = 0.69, I² = 0% (Analysis 5.2.3), respectively). The NNT was 18 (95% CI 12 to 50) for European countries. No statistically significant subgroup difference was seen between the three regions (P = 0.85).


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Subgroup analyses by baseline PUD or FD

Subgroup analyses by risk of bias: overall

Within the 17 studies in this group, six of them did not specify the type of baseline diseases. Five studies only enrolled patients with PUD or a history of PUD, and two studies only enrolled patients with FD at baseline. Four studies provided raw data of H. pylori eradication rates for patients with PUD and non-PUD for 10 versus 7 days (Calvet 2005a; Ching 1998; De Francesco 2004; Vakil 2004). Although two of the studies randomised all patients entering the study but did not randomise patients stratified by baseline disease (Ching 1998; De Francesco 2004), the PUD distribution was comparable between the two groups in these studies. We therefore performed subgroup analysis in patients with PUD and non-PUD (Analysis 5.3). In patients with PUD the eradication rate was not significantly different between 10 days and 7 days (9 studies, n =1672), with RR for H. pylori persistence of 0.87 (95% CI 0.72 to 1.05) and no significant heterogeneity between studies (P = 0.88, I² = 0%) (Analysis 5.3.1). The RR was 0.83 (0.65 to 1.05) when using a fixed-effect model. The RR for H. pylori eradication was 1.04 (95% CI 0.99 to 1.09) when H. pylori eradication was specified as the outcome, and the OR was 0.83 (95% CI 0.65 to 1.06). In patients with non-PUD a significantly increased eradication rate was seen with 10 versus 7 days (n = 6), with a RR for H. pylori persistence of 0.74 (95% CI 0.57 to 0.95), NNT = 14 (95% CI 9 to 70) with no significant heterogeneity between studies (P = 0.95, I² = 0%) (Analysis 5.3.2). The RR was 0.74 (95% CI 0.58 to 0.95) when using a fixed-effect model. The RR for H. pylori eradication was 1.06 (95% CI 0.99 to 1.15) when H. pylori eradication was used as the outcome measure and the OR for H.pylori persistence was 0.66 (95% CI 0.47 to 0.93). There was no significant difference between the subgroups of PUD and nonPUD diseases (P = 0.30). For the remaining studies that mixed patients with PUD and FD but without raw data for subgroup or without specifying the baseline disease (n = 6), the RR for H. pylori persistence was 0.73 (95% CI 0.57 to 0.94), NNT = 15 (95% CI 9 to 68) with no significant heterogeneity between studies (P = 1.00, I² = 0%) (Analysis 5.3.3).

When all risk domains were considered, eight studies were considered to have a high risk of bias (n = 1698) and nine studies were considered to have an unclear risk of bias (n = 1573). The H. pylori eradication rate was significantly increased with 14 days treatment in both subgroups (80.1% versus 77.0%, and 80.0% versus 75.3%) with RR for H. pylori persistence of 0.79 (95% CI 0.66 to 0.95) and 0.81 (95% CI 0.67 to 0.98), respectively (Analysis 5.5). The NNT was 21 (95% CI 13 to 84) and 21 (95% CI 12 to 174), respectively. No significant heterogeneity was found in either subgroup (I² = 0%, P = 0.99 and I² = 0%, P = 0.98), and no significant subgroup differences were found (P = 0.84).

Subgroup analyses by risk of bias: allocation concealment Three study (n = 1098) were judged to have an appropriate allocation concealment (Calvet 2005a; Filipec Kanizaj 2009; Vakil 2004 ) and one (n = 300) reported no allocation concealment (Gisbert 2005a). Thirteen studies had an unclear risk of bias for allocation concealment, the RR for H. pylori persistence was 0.76 (95% CI 0.64 to 0.91), NNT = 18(95% CI 12 to 45) (test for heterogeneity P = 1.00, I² = 0%; 13 studies, n = 1837). No significant difference between durations was seen for low risk (RR 0.84, 95% CI 0.68 to 1.04) or high risk studies (RR 0.91, 95% CI 0.59 to 1.41) (Analysis 5.4). No significant subgroup differences were found (P = 0.65).

Sensitivity analysis Two studies (Cho 2001; Kang 2000a) were excluded from the sensitivity analysis because it was unclear whether the reported patient samples were from the ITT sample. The PUD subgroup from one study (Ching 1998) was excluded from the sensitivity analysis as well, because H. pylori was assessed one week after omeprazole 20 mg od (Characteristics of included studies). The results were similar when these trials were excluded, with RR for H. pylori persistence of 0.80 (95% CI 0.70 to 0.92), NNT = 21 (95% CI 14 to 53) (15 studies, n = 2759), with no significant heterogeneity between studies (P = 1.00, I² = 0%). If the eradication data from the authors’ ITT definition was used instead of our strict ITT data in one study (Vakil 2004), similar results were seen, either in the analysis of all studies (RR 0.80, 95% CI 0.70 to 0.91; NNT = 21, 95% CI 14 to 46; test for heterogeneity P = 1.00, I² = 0%, n = 3259), or in the sensitivity analysis after excluding two RCTs and one PUD arm (RR 0.80, 95% CI 0.69 to 0.92; NNT = 21, 95% CI 13 to 51; test for heterogeneity P = 1.00, I² = 0%, n = 2747).

Publication bias and other small study effects The overview of the funnel plot and results of the tests for funnel plot asymmetry indicated that there was no evidence for publication bias or other small study effects in the subgroup of 10 versus 7 days. Begg-Mazumdar test Kendall’s tau = -0.09, P = 0.60; for Egger’s test bias = -0.31 (95% CI -0.94 to 0.31), P = 0.30; for Horbold-Egger test, bias = -0.29 (92.5% CI -0.85 to 0.28), P = 0.34.

1.2.2. PCN triple therapy, 10 versus 7 days Only two studies (n = 148) compared H. pylori eradication rate with PCN triple therapy for 10 days with 7 days (Di Mario 2003a; Hurenkamp 2000). The nitroimidazole used was tinidazole 500 mg bid in one (Di Mario 2003a) and metronidazole 400 mg bid in the other (Hurenkamp 2000). The PPI used was rabeprazole and omeprazole respectively, and the dose for clarithromycin was


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500 mg and 250 mg bid in the two studies, respectively. The eradication rate was not significantly different between the 10 days and 7 days group in both studies or in combination (78.9% versus 77.9%), with a RR of 1.03 (95% CI 0.56 to 1.90), 0.52 (95% CI 0.05 to 5.38), and 0.99 (95% CI 0.55 to 1.79), respectively (Analysis 8.1). One study was a single-centre study from Italy (Di Mario 2003a) and the other was a multicentre study from the Netherlands (Hurenkamp 2000). One study included patients with PUD or gastritis (all had dyspeptic symptoms) (Di Mario 2003a), and the other study included patients with active or previous PUD (Hurenkamp 2000). Both studies were judged to have unclear allocation concealment, but one study was considered to have a high risk of bias for blinding of participants and personnel (Di Mario 2003a), and the other study was considered to have an unclear risk of bias study (Hurenkamp 2000). No sensitivity analysis was necessary. It was not possible to assess funnel plot asymmetry as only two studies were available for this subgroup.

1.2.3. PAN triple therapy, 10 versus 7 days Four studies (n = 573) compared H. pylori eradication rate with PAN triple therapy for 10 days with 7 days (Berrutti 2008; Filipec Kanizaj 2009; Katicic 1997; Pellicano 2002). Eradication rate was not significantly increased from 7 days (70.9%) to 10 days (75.1%), with a RR for H. pylori persistence of 0.85 (95% CI 0.65 to 1.12). No significant heterogeneity was seen between studies (P = 0.76, I² = 0%) (Analysis 2.1).

Subgroup analysis

Subgroup analyses by regimen All studies used PPI, amoxicillin twice daily at standard doses. Three studies used metronidazole 500 mg bid, with a RR for H. pylori persistence of 0.82 (95% CI 0.61 to 1.11) (Filipec Kanizaj 2009; Katicic 1997; Pellicano 2002). One study examined the effect of metronidazole 250 mg qid and tinidazole 500 mg bid (Berrutti 2008); with a RR for H. pylori persistence of 1.11 (95% CI 0.45 to 2.76) and 0.89 (95% CI 0.34 to 2.30), respectively (Analysis 10.1). No significant subgroup differences were seen (P = 0.83).

Subgroup analyses by geographic location All studies were from European countries, therefore, no subgroup analysis for location was performed.

Subgroup analyses by baseline PUD or FD Only one study enrolled Italian patients with a history of recurrent DU (Pellicano 2002). Two studies enrolled patients with PUD or FD (Filipec Kanizaj 2009; Katicic 1997), and one study included H. pylori infected patients without baseline information (Berrutti 2008). No significant difference was found between 10 days and 7 days for both subgroups, with RR for H. pylori persistence of 1.07 (95% CI 0.58 to 1.99) for the only PUD study, and RR of 0.81 (95% CI 0.60 to 1.09) for the three studies with mixed patients with PUD and FD or without baseline disease information (Analysis 10.3). No significant subgroup differences were seen (P = 0.42).

Subgroup analyses by risk of bias: allocation concealment Two studies were judged to have a low risk of bias for allocation concealment (Berrutti 2008; Filipec Kanizaj 2009) while two studies were considered to have an unclear risk of bias for allocation concealment. No significant difference was found between 10 days and 7 days for both subgroups, with RR for H. pylori persistence of 0.85 (95% CI 0.58 to 1.24) for the low risk subgroup, and RR of 0.86 (95% CI 0.58 to 1.25) for the unclear risk subgroup (Analysis 10.4). No significant subgroup differences were seen (P = 0.98).

Subgroup analyses by risk of bias: overall When all risk domains were considered, two studies were considered to have a high risk of bias (Berrutti 2008; Pellicano 2002) and two studies were considered to have an unclear risk of bias (Filipec Kanizaj 2009; Katicic 1997). The H. pylori eradication rate was not significantly different between 10 days and 7 days in both subgroups, with RR for H. pylori persistent of 1.04 (95% CI 0.66 to 1.63) and 0.76 (95% CI 0.55 to 1.07), respectively (Analysis 10.5). No significant subgroup differences were seen (P = 0.29). Sensitivity analysis No sensitivity analysis was necessary for this subgroup of studies. Publication bias and other small study effects It was not possible to assess funnel plot asymmetry as only four studies were available for this subgroup.

1.2.4. PAQ triple therapy, 10 versus 7 days Only two studies reported data for PAQ triple therapy 10 days vs 7 days (Bago 2010; Sacco 2010). One study was from Italy, where 196 patients with FD or DU were randomised to esomeprazole 20 mg + amoxicillin 1 g + moxifloxacin 400 mg twice daily for 7 or 10 days (Sacco 2010). The other study was from Croatia and randomised 150 patients with FD to lansoprazole 30 mg +


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moxifloxacin 200 mg bid twice daily for 7 or 10 days (Bago 2010). When the data from the two studies were pooled, H. pylori eradication increased from 7 days (78.5%) to 10 days (87.6%), with a RR for H. pylori persistence of 0.58 (95% CI 0.36 to 0.95) (Analysis 2.1). The 95% CI was very close to 1. The OR was 0.51 (95% CI 0.29 to 0.92) using a random-effects model; RR for H. pylori was 0.57 (95% CI 0.35 to 0.94) when using a fixed-effect model, RR for H. pylori eradication was 1.12 (95% CI 1.02 to 1.23). The NNT was 7 (95% CI 5 to 59) (test for heterogeneity P = 0.53, I² = 0%). Subgroup analyses Both studies were from European countries, and were considered to have an unclear risk of bias for allocation concealment .and to have a high risk of bias due to blinding of participants and personnel. The two studies used different regimens, were conducted in different locations and recruited patients with different baseline diseases. RR for H. pylori persistence was 0.49 (95% CI 0.23 to 1.02) for the Italian study (Sacco 2010), and 0.67 (95% CI 0.35 to 1.29) for the Croatian study (Bago 2010). No further subgroup analyses were necessary (Analysis 13.1).

Sensitivity analysis No sensitivity analysis was necessary for this subgroup of studies.

Publication bias and other small study effects It was not possible to assess funnel plot asymmetry as only two studies were available for this subgroup.

1.2.5. PANi triple therapy, 10 versus 7 days Only one study reported data for PPI + amoxicillin + a nitrofuran 10 days versus 7 days (Lv 2011). It was a multicentre study from China, in which 300 infected DU patients were randomised to

rabeprazole 10 mg, amoxicillin 1 g, furazolidone 100 mg bid for 7 or 10 days. The H. pylori eradication rate was not significantly increased from 7 days (73.8%) to 10 days (79.3%) for rabeprazole + amoxicillin + furazolidone 1 (n = 290), with RR of 0.79 (95% CI 0.52 to 1.20) (Analysis 2.1). This study was considered to have an unclear risk of bias. 1.3. PPI triple therapy 14 days versus 10 days In total, 12 studies (n = 2111) with 14 comparisons were analysed under two different regimen subgroups (PCA and PCN). Two studies provided two comparisons in two different antibiotics regimen groups (Filipec Kanizaj 2009; Katicic 1997). One study had two arms in the same PPI + amoxicillin + a nitroimidazole regimen but studied two different nitroimidazoles (metronidazole 250 mg qid or tinidazole 500 mg bid) (Berrutti 2008), which were combined into one comparison for PCN analysis. Regardless of type and dose of antibiotics, increased duration of PPI triple therapy from 10 days to 14 days significantly increased the H. pylori eradication rate (78.5% versus 84.4%; RR for H. pylori persistence 0.72, 95% CI 0.58 to 0.90; NNT 17, 95% CI 11 to 46) without significant heterogeneity (test for heterogeneity P = 0.23, I² = 20%) (Analysis 3.1). The overview of the funnel plot and results of the tests for funnel plot asymmetry indicated that there might be evidence for publication bias or other small study effects for PPI triple therapy 14 versus 10 days, only when studies were analysed as separated by the regimens used (12 studies 14 comparisons). Begg-Mazumdar test Kendall’s tau = -0.45, P = 0.02; for Egger’s test bias = -1.92 (95% CI -3.73 to 0.11), P = 0.04; for Horbold-Egger test, bias = -1.48 (92.5% CI -3.68 to 0.72), P = 0.21 (Figure 5). When the different regimens from the same studies were combined (12 studies and 12 comparisons), no significant publication bias or other small study effect was seen. Begg-Mazumdar test Kendall’s tau = -0.33, P = 0.12; for Egger’s test bias = -1.54 (95% CI -4.06 to 0.97), P = 0.20; for Horbold-Egger test, bias = -0.60 (92.5% CI -3.18 to 1.98), P = 0.65.


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Figure 5. Funnel plot of comparison: 3 PPI + two antibiotics triple therapy, 14 days versus 10 days, main analyses, outcome: 3.1 H. pylori persistence, subgroup by antibiotics regimen, regardless of dose.

1.3.1 PCA 14 days versus 10 days Ten studies (n = 1596) compared PCA for 14 days versus 10 days. H. pylori eradication rate was significantly increased for 14 days (85.8%) versus 10 days (79.7%); RR for H. pylori persistence 0.69 (95% CI 0.52 to 0.91; NNT 16, 95% CI 10 to 54); moderate heterogeneity was seen between studies (P = 0.20, I² = 27%) ( Analysis 3.1).

Subgroup analysis

Subgroup analyses by geographic location Three studies were from Asia (n = 483), three from Europe (n = 729) and two from North America (both from the US, n = 384). Subgroup analysis of geographic regions showed that RR for H. pylori persistence was 0.46 (95% CI 0.29 to 0.74; NNT = 9, 95% CI 7 to 20), 0.71 (95% CI 0.45 to 1.11) and 0.93 (95% CI 0.63 to 1.37) for Asian countries, European countries, and the US, respectively. The test for heterogeneity showed no significant or moderate heterogeneity (P = 0.70, I² = 0%; P = 0.17, I² = 38%; and P = 0.80, I² = 0%, respectively). No significant statistical heterogeneity was suggested between the three regions (P = 0.08) (Analysis 6.2).

Subgroup analyses by regimen All studies in this group used a standard dose of PPIs and antibiotics bid, except one Korean study where the type and dose of PPI was not clear (Park 2009a). RR for H. pylori persistence was 0.68 (95% CI 0.50 to 0.92) for the nine studies (n = 1540) that used PPI and two antibiotics twice daily at standard doses, NNT = 15 (95% CI 10 to 59); moderate heterogeneity was seen between studies (P = 0.14, I² = 35%) (Analysis 6.1).

Subgroup analyses by baseline PUD or FD Within the 10 studies in this group, five studies only enrolled patients with PUD or a history of PUD (n = 950) and five studies enrolled both patients with PUD and with FD or did not provide baseline information (n = 646) (Analysis 6.3). In the five studies of PUD, there was a trend for the eradication rate to be increased from 10 to 14 days (77.7% versus 83.3%) but this was not statistically


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significant with a RR for H. pylori persistence of 0.73 (95% CI 0.50 to 1.09) with significant heterogeneity between studies (P = 0.10, I² = 49%) (Analysis 6.3.1). In studies including both participants with PUD or FD or unclear baseline diseases, the eradication rate was significantly increased from 10 to 14 days (82.3% versus 90%), with a RR for H. pylori persistence of 0.59 (95% CI 0.38 to 0.90) (NNT = 14, 95% CI 9 to 57), with no significant heterogeneity between studies (P = 0.51, I² = 0%) (Analysis 6.3.2). No significant subgroup difference was suggested between the two subgroups (P = 0.28).

Subgroup analyses by risk of bias: allocation concealment All studies in this group were judged to have an unclear risk of bias for allocation concealment except one, which was considered tobe low risk (Filipec Kanizaj 2009) (Analysis 6.4). The RR for H. pylori persistence was 0.73 (95% 0.57 to 0.94) for studies with an unclear risk of bias (9 studies, n = 1421, NNT = 18, 95% CI 11 to 76, test for heterogeneity P = 0.20, I² = 27%), while the RR was 0.21 (95% CI 0.05 to 0.86) for the only study assessed to have a low risk of bias for allocation concealment.

Subgroup analyses by risk of bias: overall When all risk domains were considered, three studies were considered to have a high risk (Karatapanis 2011; Mantzaris 1999; Palmas 2002) and seven studies were considered to have an unclear risk of bias (Analysis 6.5). The H. pylori eradication rate was not significantly different between 14 days and 10 days in the high risk subgroup (82.8% versus 78.9%), with a RR for H. pylori persistence of 0.80 (95% CI 0.49 to 1.30) (test for heterogeneity I² = 33%, P = 0.23). The H. pylori eradication rate was significantly different between 14 days and 10 days in the unclear risk subgroup (87.1% versus 79.9%), with a RR for H. pylori persistence of 0.62 (95% CI 0.43 to 0.90) (test for heterogeneity I² = 33%, P = 0.18). The NNT was 13 (95% CI 9 to 51). No significant subgroup differences were found between the high and unclear risk of bias subgroups (P = 0.50).

Sensitivity analysis Two Asian studies (Cho 2001; Kang 2000a) were excluded from the sensitivity analysis because it was unclear whether the reported patient samples were from the ITT sample. The difference between 14 days versus 10 days became non-significant, with a RR for H. pylori persistence of RR 0.81 (95% CI 0.62 to 1.05, 8 studies, n = 1169; test for heterogeneity P = 0.40, I² = 4%). If the eradication data from the authors’ ITT definition was used instead of our strict ITT data, in one study (Fennerty 1998) a significant difference was still seen for the 14 versus 10 days groups, in the analysis of all studies (RR for H. pylori persistence 0.68, 95%

CI 0.51 to 0.91; NNT 16, 95% CI 10 to 56; test for heterogeneity P = 0.22, I² = 24%; n = 1573), but not in the sensitivity analysis after excluding two Asian RCTs (Cho 2001; Kang 2000a) (RR 0.80, 95% CI 0.61 to 1.06; test for heterogeneity P = 0.40, I² = 4%; n = 1146).

Publication bias and other small study effects The overview of the funnel plot and results of the tests for funnel plot asymmetry indicated that there was no evidence for publication bias or other small study effects for the outcome of H. pylori persistence for the PCA 14 versus 10 days. Begg-Mazumdar test Kendall’s tau = -0.42, P = 0.07; for Egger’s test bias = -1.62 (95% CI -3.86 to 0.63) , P = 0.13; for Horbold-Egger test, bias = -1.29 (92.5% CI -3.79 to 1.22), P = 0.33.

1.3.2 PAN 14 days versus 10 days Four studies (n = 515) compared H. pylori eradication rate with PAN triple therapy for 14 days with 10 days. H. pylori eradication rate was not significantly increased from 10 days (75.1%) to 14 days (79.5%); with a RR for H. pylori persistence of 0.79 (95% CI 0.54 to 1.15). No significant heterogeneity was seen between studies (P = 0.30, I² = 18%) (Analysis 3.1).

Subgroup analysis

Subgroup analyses by regimen Three studies used PPI bid, metronidazole 500 mg bid, and amoxicillin 1 g bid (Filipec Kanizaj 2009; Katicic 1997; Pellicano 2002), but metronidazole was used for only 10 days in the 14 days group in one study (Katicic 1997). One study provided data for two different subgroups, with PPI and amoxicillin used twice daily at standard doses, and metronidazole 250 mg qid or tinidazole 500 mg bid (Berrutti 2008). No significant difference was seen for H. pylori eradication rate, with a RR for H. pylori persistence of 0.71 (95% 0.43 to 1.17, n = 401), 1.02 (95% CI 0.44 to 2.39, n = 61), 0.96 (95% CI 0.36 to 2.61, n = 53), respectively (Analysis 11.1). No significant subgroup differences were seen (P = 0.74).

Subgroup analyses by geographic location All four studies were European, therefore no subgroup analysis for location was performed.


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Subgroup analyses by baseline PUD or FD

2. PPI + bismuth + two antibiotics quadruple therapy

Only one study included only patients with PUD (n = 106) ( Pellicano 2002). Other studies (n = 409) mixed patients with FD and PUD (Filipec Kanizaj 2009; Katicic 1997) or did not specify baseline disease (Berrutti 2008). The H. pylori eradication rate was not significantly increased from 10 days to 14 days; with a RR for H. pylori persistence of 0.93 (95% CI 0.50 to 1.74) for the PUD study and 0.72 (95% CI 0.42 to 1.23) for other studies (Analysis 11.3). No significant subgroup differences was seen (P = 0.57).

Only six studies (n = 1157) provided data for PPI + bismuth + two antibiotics quadruple therapy. H. pylori eradication was compared for 14 days versus 7 days, 10 days versus 7 days, and 14 versus 10 days, respectively (Analysis 14.1; Analysis 15.1; Analysis 16.1).

Subgroup analyses by risk of bias: allocation concealment Two studies in this group were judged to have an unclear risk of bias for allocation concealment (Katicic 1997; Pellicano 2002) and two were considered to have a low risk of bias for allocation concealment (Berrutti 2008; Filipec Kanizaj 2009) . The RR for H. pylori persistence was 0.62 (95% 0.21 to 1.86) for studies with unclear risk of bias (, while the RR was 0.85 (95% CI 0.55 to 1.30) for the only study that had a low risk of bias for allocation concealment (Analysis 11.4). No significant subgroup differences were seen (P = 0.60).

Subgroup analyses by risk of bias: overall When all risk domains were considered, one study (Pellicano 2002) was considered to have a high risk of bias for selective reporting and one study was considered to have a high risk of bias for blinding of participants and personnel (Berrutti 2008). Two other studies were considered to have an unclear risk of bias (Analysis 11.5). The H. pylori eradication rate was not significantly different between 14 days and 10 days in both subgroups, with a RR for H. pylori persistence of 0.97 (95% CI 0.62 to 1.51), and 0.57 (95% CI 0.25 to 1.29), respectively. No significant subgroup differences were seen (P = 0.22).

Sensitivity analysis Sensitivity analysis was performed by excluding the study that used metronidazole 10 days in the 14 days group (Katicic 1997). The RR for the remaining study was 0.76 (95% CI 0.43 to 1.36; test for heterogeneity P = 0.16, I² = 46%).

Publication bias and other small study effects It was not possible to assess funnel plot asymmetry as only four studies were available for this subgroup.

2.1. PPI bismuth quadruple therapy 14 days versus 7 days Three studies reported data for PPI bismuth quadruple therapy 14 days versus 7 days with 362 patients; two were from Iran (Daghaghzadeh 2007; Emami 2006) and one from China (Sun 2010). One study randomised patients with PUD or FD to omeprazole 20 mg, bismuth 240 mg, tetracycline 750 mg and metronidazole 500 mg twice daily for 14 or 7 days (Emami 2006). The second study randomised patients with PUD or dyspeptic chronic active gastritis to omeprazole 20 mg, bismuth subcitrate 240 mg, furazolidone 200 mg, and amoxicillin 1 g twice daily for 14 or 7 days (Daghaghzadeh 2007). The third study randomised patients with FD patients to omeprazole 20 mg, bismuth potassium citrate 220 mg, clarithromycin 500 mg, and amoxicillin 1 g twice daily for 14 versus 7 days (Sun 2010). Pooled H. pylori eradication was not significantly increased with 14 days (77.9%) compared with 7 days (69.1%), with a pooled RR for H. pylori persistence of 0.71 (95% CI 0.44 to 1.15); moderate heterogeneity was seen (P = 0.12, I² = 54%) (Analysis 14.1). All studies were from Asian countries, and all were considered to have an unclear risk of bias for allocation concealment. Therefore no subgroup analysis was necessary for location and risk of bias. Subgroup analysis was only performed for the Chinese FD study and the two Iranian mixed PUD and FD studies, with RR for H. pylori persistence of 0.31 (95% CI 0.12 to 0.81; n = 160) and 0.84 (95% CI 0.62 to 1.15; n = 202), respectively. The NNT was 7 (95% CI 6 to 27) for the Chinese FD study (Sun 2010), test for subgroup differences P = 0.05 (Analysis 14.3). One study was considered to have a high risk of bias for blinding of participants and personnel (Sun 2010); the other two studies had an unclear risk (Analysis 14.4). The RRs for H. pylori persistence were 0.31 (95% CI 0.12 to 0.81; n = 160) and 0.84 (95% CI 0.62 to 1.15; n = 202), respectively. One study was excluded from the sensitivity analysis because the post-treatment H. pylori assessment was performed after eight weeks, which was six weeks antibiotic free but only two weeks famotidine free (Emami 2006). The RR for H. pylori persistence was 0.59 (95% CI 0.20 to 1.77); significant heterogeneity was seen (P = 0.04, I² = 76%). It was not possible to assess funnel plot asymmetry as only three studies were available for this subgroup. 2.2. PPI bismuth quadruple therapy 10 days versus 7 days Only two studies, both from China, provided data for PPI bismuth quadruple therapy for 10 days or 7 days (n = 378). One study randomised patients with dyspepsia to pantoprazole 40 mg, colloidal


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bismuth subcitrate 220 mg and tetracycline 750 mg twice daily for 10 or 7 days (Zheng 2009). The other study randomised patients with DU to rabeprazole 10 mg, bismuth 220 mg, amoxicillin 1 g, and furazolidone 100 mg twice daily for 10 or 7 days (Lv 2011). The H. pylori eradication rate was not significantly different between 10 days and 7 days, either in the individual studies or in the pooled analysis (87.4% versus 81.9%), with RRs for H. pylori persistence of 0.53 (95% CI 0.19 to 1.46), 0.76 (95% CI 0.44 to 1.32), and 0.70 (95% CI 0.43 to 1.14), respectively. Homogeneity between studies was seen (P = 0.54, I² = 0%) (Analysis 15.1). Both studies were considered to have an unclear risk of bias for allocation concealment. One study was considered to have a high risk of bias for blinding of participants and personnel (Zheng 2009) and the other study was of unclear risk (Lv 2011). No further subgroup analysis or sensitivity analysis were performed. Funnel plot asymmetry was not assessed because there were only two studies in this group. 2.3. PPI bismuth quadruple therapy 14 days versus 10 days Only one study provided data for PPI bismuth quadruple therapy for 14 days or 10 days (n = 417) (Dore 2011). This was an Italian study in which 417 patients with dyspeptic symptoms, and who were diagnosed with H. pylori infection, underwent upper endoscopy (3.8% of them were PUD) and were then randomised to pantoprazole 20 mg, bismuth subcitrate 240 mg, tetracycline 500 mg, and metronidazole 500 mg twice daily for 14 days or 10 days. Allocation concealment was at low risk of bias. However, this study was considered to have a high risk of bias because it was an open-label study with blinding, and it is unclear how the authors excluded patients who self-reported adverse events from the adverse event outcome. The H. pylori eradication rate was not significantly different between 14 days (91.6%) and 10 days (92.6%), with a RR for H. pylori persistence of 1.13 (95% CI 0.59 to 2.18) (Analysis 16.1). 3. PPI + three antibiotics quadruple therapy

for H. pylori persistence of 1.11 (95% CI 0.47 to 2.60) (Analysis 17.1).

4. PPI + one antibiotic dual therapy

Only two studies (n = 144) provided data for PPI dual therapy; and compared H. pylori eradication for 14 days versus 7 days (Chew 1994) and 10 days versus 7 days (Di Caro 2002a), respectively (Analysis 18.1; Analysis 19.1).

4.1. PPI dual therapy 14 days versus 7 days One study from Canada randomised 64 infected patients with or without DU to high dose PPI (omeprazole 60 mg bid) plus clarithromycin 500 mg bid for 14 days versus 7 days (Chew 1994). No significant difference was shown for the H. pylori eradication rate between 14 days (67.7%) and 7 days (72.7%), with a RR for H. pylori persistence of 1.18 (95% CI 0.56 to 2.52) (Analysis 18.1). This was a conference abstract with an unclear risk of bias for allocation concealment.

4.2. PPI dual therapy 10 days versus 7 days One study from Italy randomised 80 infected patients with or without PUD to rabeprazole 20 mg od plus levofloxacin 500 mg od for 10 days or 7 days (Di Caro 2002a). No significant difference in the rate of H. pylori eradication was seen between 10 days (65.0%) and 7 days (70.0%), with a RR for H. pylori persistence of 1.17 (95% CI 0.62 to 2.20) (Analysis 19.1). The risk of bias for allocation concealment was considered low, but this study was considered to have a high risk of bias due to the open-label design.

5. H2 RA + bismuth-based quadruple therapy

Three studies reported data for H2 RA bismuth quadruple therapy. One was H2 RA + bismuth + two antibiotics for 14 versus 7 days (Kaviani 2001), and two were RBC + two antibiotics for 10 versus 7 days (Knigge 1999; Savarino 1999) (Analysis 20.1; Analysis 21.1).

PPI + three antibiotics quadruple therapy 10 days versus 7 days Only one study provided data for PPI + three antibiotics quadruple therapy and the duration investigated was 10 days versus 7 days (Basu 2011). On hundred and eighty dyspeptic patients with H. pylori-induced gastritis were randomised to omeprazole 40 mg once daily, levofloxacin 250 mg once daily, nitazoxanide 500 mg twice daily, and doxycycline 100 mg once daily for 10 days or 7 days. This study was considered to have a low risk of bias for allocation concealment but a high risk of bias being an open-label study, having selective reporting and inconsistent data (Characteristics of included studies). The H. pylori eradication was not significantly different between 10 days (88.9%) and 7 days (90.0%), with a RR

5.1. H2 RA + bismuth + two antibiotics quadruple therapy 14 versus 7 days One Iranian two-centre study randomised patients with DU or pre-pyloric ulcer to ranitidine 300mg bid, bismuth subcitrate 240mg bid, amoxicillin 1g bid and metronidazole 500mg bid for 14 or 7 days (n = 160). Allocation concealment was judged to have a low risk of bias in this study (Kaviani 2001). Although the eradication rate was low in both arms, it was significantly increased with 14 days compared to 7 days (62.5% versus 23.8%), RR for H. pylori persistence of 0.49 (95% CI 0.36 to 0.67), and the NNT was 3 (95% CI 2 to 4) (Analysis 20.1).


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5.2. RBC + two antibiotics 10 versus 7 days Two studies (n = 215) in the group of H2 RA bismuth quadruple therapy compared 10 versus 7 days, and both used RBC 400 mg bid as the H2 RA bismuth compound; antibiotics used were metronidazole 500 mg + tetracycline 500 mg bid and metronidazole 500 mg bid + clarithromycin 250 mg bid, respectively (Knigge 1999; Savarino 1999). One study enrolled US patients with H. pylori infection but without baseline disease details (Knigge 1999) and the other study enrolled Italian patients with FD and H. pylori infection (Savarino 1999). Both studies were judged to have a low and unclear risk of bias for allocation concealment, respectively. However, both studies were considered to have a high risk of bias of selective reporting (Knigge 1999) and due to an openlabel study design (Savarino 1999). H. pylori eradication was not significantly different between 10 days and 7 days, in both studies or in the combined analysis (73.6% versus 69.7%), with a RR for H. pylori persistence of 0.88 (95% CI 0.59 to 1.32) with no significant heterogeneity between studies (P = 0.99, I² = 0%) (Analysis 21.1).

6. H2 RA bismuth triple therapy

H2 RA bismuth triple therapy 14 days versus 7 day Two studies compared 14 days with 7 days of H2 RA bismuth triple therapy with 232 participants. One study randomised Brazilian patients with PUD (Mesquita 2005) and the other study randomised Italian patients with DU (Pozzato 1998). Both regimens were RBC 400 mg bid plus clarithromycin 500 mg bid, and both studies used RBC for four weeks in both groups. The H. pylori eradication rate was not significantly different between 14 days and 10 days (78.1% versus 73.7% ), with a RR forH. pylori persistence of 0.84 (95% CI 0.53 to 1.33); no significant heterogeneity was seen (test for heterogeneity P = 0.81, I² = 0%). No other durations were compared for H2 RA bismuth triple therapy (Analysis 22.1). Allocation concealment was unclear in both studies. However, both studies were considered to have a high risk of bias due to an open study design.

7. H2 RA triple therapy (H2 RA + two antibiotics)

famotidine 40 mg bid, amoxicillin 1 g bid, and tinidazole 500 mg bid for 14 or 7 days (Hsu 2005). The third was a South Korean multicentre study of 234 patients with PUD randomised to lafutidine 20 mg bid, clarithromycin 500 mg bid, and amoxicillin 1000 mg bid for 14 days or 7 days (Kim 2008). The rate of eradication was not significantly increased with 14 days when the studies were combined (79.3% versus 70%), RR for H. pylori persistence of 0.64 (95% CI 0.40 to 1.03) with medium heterogeneity (test for heterogeneity P = 0.17, I² = 44%) (Analysis 23.1).

Subgroup analysis

Subgroup analysis by regimen All three studies examined three different antibiotic regimens. Significant H. pylori eradication difference between 14 days and 7 days was seen for H2 RA + amoxicillin + metronidazole (Hu 2003) (RR for H. pylori persistence 0.42, 95% CI 0.19 to 0.93; NNT 4, 95% CI 3 to 34) and marginal significance was seen for H2 RA + amoxicillin 1 g bid, tinidazole 500 mg (Hsu 2005) (RR 0.55, 95% CI 0.30 to 1.00, P = 0.05; NNT 6, 95% CI 4 to 4545). No significant difference was seen for H2 RA + clarithromycin + amoxicillin (Kim 2008) (RR 0.93, 95% CI 0.58 to 1.49) (Analysis 23.1).

Subgroup analysis by geographic location All three studies were from East Asia. No subgroup analysis was necessary.

Subgroup analysis by baseline disease One study included only patients with PUD (Kim 2008), with a RR for H. pylori persistence of 0.93 (95% CI 0.58 to 1.49); the other two studies mixed patients with PUD, FD, or gastritis (Hsu 2005; Hu 2003), with a RR of 0.50 (95% CI 0.31 to 0.80) and NNT = 5 (95% CI 4 to 13) (Analysis 23.3). The test for subgroup differences was not significant (P = 0.07).

H2 RA triple therapy (H2 RA + two antibiotics) 14 days versus 7 days

Subgroup analysis by risk of bias: allocation concealment

Three studies reported data for H2 RA triple therapy regimens of 14 versus 7 days with 417 participants. One was a Chinese multicentre trial that randomised patients with gastritis or DU to famotidine 20 mg bid, amoxicillin 1 g bid, and metronidazole 400 mg bid for 14 days or 7 days (Hu 2003); the second was a Taiwanese single-centre study that randomised patients with PUD or FD to

Only one study was assessed to have a low risk of bias for allocation concealment (Kim 2008), with a RR for H. pylori persistence of 0.93 (95% CI 0.58 to 1.49); the other two studies were considered to have an unclear risk of bias (Hsu 2005; Hu 2003), with a RR of 0.50 (95% CI 0.31 to 0.80) (Analysis 23.4), NNT = 5 (95% CI 4 to 13) (test for subgroup differences P = 0.07).


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Subgroup analysis by risk of bias: overall

Subgroup analysis

When all risk domains were considered, one study was considered to have a low risk of bias (Kim 2008), and two studies were considered to have a high risk of bias due to allocation concealment and selective reporting (Hu 2003) and a high risk of bias for blinding of participants and personnel (Hsu 2005). The subgroup analysis was the same as that for allocation concealment (Analysis 23.5).

The two studies used two different regimens, both of which did not show a significant H. pylori eradication rate between 14 days and 7 days (Analysis 24.1.1; Analysis 24.1.2). One study involved patients with FD (Muszynki 1992) while the other study involved patients with PUD (de Boer 1994). Both studies were from Europe and both were assessed to have an unclear risk of bias for allocation concealment. One study was considered to have a high risk of bias because it was at a high risk for having incomplete outcome data (Muszynki 1992) while the other study was of unclear risk (de Boer 1994). No further subgroup analysis was performed. No sensitivity analysis was necessary. Assessment of publication bias was not possible as only two studies were available for this subgroup. No other durations were compared for bismuth triple therapy.

Sensitivity analysis The upper CI of RR 0.64 for H. pylori persistence was very close to 1 (95% CI 0.40 to 1.03) therefore a sensitivity analyses was performed. When a fixed-effect model was used, the RR for H. pylori persistence was 0.69 (95% CI 0.49 to 0.96). When H. pylori eradication was the outcome, the RR for H. pylori eradication was 1.18 (95% CI 0.96 to 1.45, using a random-effects model). The OR was 0.54 (95% CI 0.28 to 1.07) for a random-effects model and 0.61 (95% CI 0.39 to 0.95) for a fixed-effect model.

Publication bias and other small study effects It was not possible to assess funnel plot asymmetry as only three studies were available for this subgroup. No other durations were compared for H2 RA + two antibiotics triple therapy.

Adverse events analysis We analysed adverse events reported by the primary studies. Most of the studies did not provide information on how adverse events were collected, whether the adverse events were passively collected by patient reporting or actively collected by physicians’ questionnaire. For most of the studies, it was not clear whether the adverse events were considered as treatment-related by the investigators; and whether only those considered related to treatments were reported.

8. Bismuth triple therapy (bismuth salt + two antibiotics) 1. PPI triple therapy

Bismuth triple therapy (bismuth salt + two antibiotics) 14 days versus 7 days Only two studies compared 14 days with 7 days for bismuth salt + two antibiotics triple therapy, with 153 participants. One was a Polish single-centre trial that randomised patients with FD to bismuth subsalicylate (BSS) 250 mg bid, tetracycline 500 mg bid, and metronidazole 250 mg bid for 14 or 7 days (Muszynki 1992). The other study was a Dutch single-centre study that randomised patients with PUD to colloidal bismuth subcitrate (CBS) 120 mg bid, tetracycline 500 mg bid, and metronidazole 500 mg tid for 14 or 7 days (de Boer 1994). In this study, “most patients were either on maintenance treatment with H2 RAs or were taking H2 RAs on demand”. The authors labelled this study as “quadruple therapy” although the type and dose of H2 RAs were not known and were not the same for both groups (de Boer 1994). After discussion, we judged this study to be eligible for inclusion in the review and classed it as a bismuth triple therapy study. H. pylori eradication was not significantly different between 7 days and 14 days either in individual studies or in combination analysis (83.3% versus 86.7%; RR for H. pylori persistence 0.76, 95% CI 0.37 to 1.54; test for heterogeneity P = 0.56, I² = 0%) (Analysis 24.1).

1.1. PPI triple therapy 14 days versus 7 days Thirty-eight out of 45 studies of PPI triple therapy 14 days versus 7 days reported data for patients with adverse events or patients who discontinued therapy due to adverse events. Twenty-five studies (n = 3971) reported data for patients with adverse events for PPI triple therapy 14 days versus 7 days. When patients with adverse events were pooled, there was an increased proportion with 14 days (19.3%) versus 7 days (15.5%), with a RR of 1.20 (95% CI 1.06 to 1.37; NNTH 31, 95% CI 18 to 104). No statistical heterogeneity was noticed (Chi² = 13.50, P = 0.97; I² = 0%). No significant difference was noticed between the three subgroups (PCA, PCN, and PAN) (P = 0.42) (Analysis 1.2). Twenty-eight studies (n = 3990) reported data for patients who discontinued treatment due to adverse events. No significant difference was found between 14 days versus 7 days (2.0% versus 1.6%), with a RR of 1.14 (95% CI 0.71 to 1.82). No statistical heterogeneity was noticed (Chi² = 9.19, P = 0.96; I² = 0%), and no significant difference was noticed between the four subgroups (PCA, PCN, PAN, and PAQ) (P = 0.91) (Analysis 1.3).


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1.1.1. PCA triple therapy, 14 versus 7 days

Twenty out of 34 studies in this group reported data for patients with adverse events, which included 3225 participants. More patients in the PAC 14 days group reported adverse events than in the PAC 7 days, with a significant difference (19.6% versus 16.0%; RR 1.21, 95% CI 1.06 to 1.39; with no significant heterogeneity between studies P = 0.99, I² = 0%) (Analysis 4.6). The NNTH was 30 (95%CI 16 to 109), . Nineteen studies (n = 2705) reported data for patients who discontinued treatment due to adverse events. There was no significant difference between the two groups although a trend favoured the 7 days group (1.7% versus 1.5%; RR 1.15, 95% CI 0.63 to 2.10; test for heterogeneity P = 0.91, I² = 0%) (Analysis 4.7). The most reported adverse events (≥ 3 studies) were diarrhoea, loose stool or increasing stool passage (n = 11 studies; RR 1.05, 95% CI 0.76 to 1.44) (Analysis 4.8); taste disturbance, metallic taste or glossitis (8 studies; RR 1.67, 95% CI 1.10 to 2.52) (Analysis 4.9); nausea and vomiting (8 studies; RR 1.81, 95% CI 1.10 to 2.96) (Analysis 4.10); skin rash or itching or allergic cutaneous reaction (7 studies; RR 1.24, 95% CI 0.46 to 3.36) (Analysis 4.11); epigastric discomfort or abdominal pain (5 studies; RR 1.07, 95% CI 0.55 to 2.08) (Analysis 4.12); headache (3 studies; RR 1.73, 95% CI 0.67 to 4.44) (Analysis 4.13). Other reported adverse events included dry mouth or throat or thirsty, monilia (2 studies; RR 1.63, 95% CI 0.32 to 8.38) (Analysis 4.14); stomatitis or angular stomatitis (2 studies; RR 1.47, 95% CI 0.44 to 4.91) (Analysis 4.15); loss of appetite (2 studies; RR 0.63, 95% CI 0.12 to 3.21) (Analysis 4.16); tongue discolouration (2 studies; RR 0.45, 95% CI 0.07 to 3.03) (Analysis 4.17); dizziness (2 studies; RR 0.97, 95% CI 0.18 to 5.23) (Analysis 4.18); regurgitation or belching (2 studies; RR 0.66, 95% CI 0.08 to 5.25) (Analysis 4.19); bloating (2 studies; RR 1.08, 95% CI 0.03 to 36.21) (Analysis 4.20); discoloured faeces (1 study; RR 1.11, 95% CI 0.07 to 17.42) (Analysis 4.21); monilia (1 study; RR 1.00, 95% CI 0.06 to 15.86) (Analysis 4.22); and herpes simplex labialis (1 study; RR 2.99, 95% CI 0.12 to 73.11) (Analysis 4.23). Significant increased taste disturbance or metallic taste or glossitis, nausea or vomiting was seen with 14 days PCA triple therapy compared with 7 days (Analysis 4.9; Analysis 4.10), respectively. No significant heterogeneity was seen (P = 0.98, I² = 0%; P = 0.85, I² = 0%, respectively). The NNTH was 47 (95%CI 21 to 301) and 57 (95%CI 23 to 448), respectively . No significant difference was seen between 14 days and 7 days in regards to other adverse events, with no significant heterogeneity between studies for any comparisons with more than one study (all P > 0.10, all I² < 25%) except for the adverse event of bloating (two studies, n = 201; test for heterogeneity Chi² = 2.72, P = 0.10; I² = 63%) (Analysis 4.20). Not enough information was available to perform a subgroup analysis according to the severity of adverse events.

1.1.2. PCN triple therapy, 14 versus 7 days Only two out of four studies in this group reported raw data for patients with adverse events in 343 participants (Dal Bo’ 1998; Dammann 2000). Adverse events were similar between 14 days and 7 days (22.4% versus 19.8%; RR 1.00, 95% CI 0.67 to 1.50) with no significant heterogeneity between studies (P = 0.79, I² = 0%) (Analysis 7.5). Only two studies reported data of patients who discontinued treatment due to adverse events. Of them, one reported that no patients discontinued treatment due to adverse events (Dal Bo’ 1998); the other study provided data for patients who discontinued treatment due to severe adverse events, without a significant difference between 14 and 7 days (pooled proportion with adverse events 4.9% versus 4.4%; RR 0.92, 95% CI 0.35 to 2.46) (Paoluzi 2006) (Analysis 7.6). No study reported raw data for individual adverse events for both groups.

1.1.3. PAN triple therapy, 14 versus 7 days Four out of 10 studies in this group reported data for patients with adverse events, comprising 403 participants (Berrutti 2008; Hu 1999; Hu 2004; Wong 2000). There was no significant difference in the proportion of patients with adverse events with 14 days of therapy compared with those with 7 days of therapy (14.7% versus 7.8%; RR 1.73, 95% CI 0.84 to 3.58); no significant heterogeneity was found (P = 0.27, I² = 24%) (Analysis 9.6). Eight studies provided data for the patients who discontinued treatment due to adverse events. Of them, five reported that no patients discontinued treatment due to adverse events (Chaudhary 2004; Hu 1999; Hu 2003; Hu 2004; Wong 2000). Three studies reported that six patients discontinued treatment due to adverse events in the 14 days group versus four patients in 7 days (Berrutti 2008; Filipec Kanizaj 2009; Pellicano 2002). There was not a statistically significant difference between the 14 and 7 days groups, with a pooled proportion of patients discontinuing treatment due to adverse events in all eight studies of 1.6% versus 1.0% (RR 1.95, 95% CI 0.36 to 10.65) (Analysis 9.7). Five studies reported data for individual adverse events (Berrutti 2008; Chaudhary 2004; Filipec Kanizaj 2009; Hu 1999; Wong 2000). Adverse events reported by more than one study included diarrhoea (4 studies; RR 0.98, 95% CI 0.31 to 3.16) (Analysis 9.8), nausea or vomiting or epigastric discomfort (3 studies; RR 1.12, 95% CI 0.46 to 2.74) (Analysis 9.9), metallic taste or dysgeusia or taste disturbance (3 studies; RR 1.58, 95% CI 0.67 to 3.71) (Analysis 9.10), epigastric pain or abdominal pain (2 studies; RR 1.19, 95% CI 0.41 to 3.48) (Analysis 9.11), dizziness (2 studies; RR 1.80, 95% CI 0.24 to 13.59) (Analysis 9.12), skin rash (2 studies; RR 0.94, 95% CI 0.10 to 8.70) (Analysis 9.13), and headache (2 studies; RR 1.23, 95% CI 0.50 to 3.05) (Analysis 9.14). Other adverse events that were only reported by one study included flatulence (RR 1.30, 95% CI 0.22 to 7.55) (Analysis 9.15), malaise (RR 1.73, 95% CI 0.16 to 18.70) (Analysis 9.16),


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heartburn (RR 0.87, 95% CI 0.06 to 13.59) (Analysis 9.17), regurgitation (RR 2.60, 95% CI 0.11 to 62.89) (Analysis 9.18), pruritus (RR 2.60, 95% CI 0.11 to 62.89) (Analysis 9.19), and loss of appetite (RR 1.40, 95% CI 0.24 to 8.16) (Analysis 9.20). No significant difference was seen between 14 and 7 days in regards to all these adverse events, with no significant heterogeneity between studies for any comparison. For all tests for heterogeneity, P > 0.10, I² = 0% to 4%.

1.1.4. PAQ triple therapy, 14 versus 7 days Neither study comparing the H. pylori eradication rate of PAQ triple therapy for 14 versus 7 days (Bosques-Padilla 2004; Ercin 2010) reported raw data for patients with adverse events, but both reported data for patients who discontinued treatment due to adverse events. No significant difference was seen between 14 days and 7 days (2.5% versus 2.3%; RR 1.10, 95% CI 0.16 to 7.62) (Analysis 12.4). No significant difference was seen between 14 days and 7 days for individual adverse events, all of which were reported by only one study, including diarrhoea (Bosques-Padilla 2004) (RR 0.30, 95% CI 0.03 to 3.00) (Analysis 12.5), headache (Bosques-Padilla 2004) (RR 0.24, 95% CI 0.03 to 2.03) (Analysis 12.6), skin rash or pruritus (Bosques-Padilla 2004) (RR 0.95, 95% CI 0.06 to 14.62) (Analysis 12.7), nausea or vomiting (Ercin 2010) (RR 3.80, 95% CI 0.16 to 90.98) (Analysis 12.8), and allergic reaction (Ercin 2010) (RR 0.42, 95% CI 0.02 to 10.11) (Analysis 12.9). 1.2. PPI triple therapy 10 days versus 7 days Eleven out of 24 studies reported data for patients with adverse events for the four PPI triple therapy subgroups for 10 days versus 7 days. Pooled patients with adverse events increased with 10 days (16.2%) versus 7 days (15.3%), with a RR of 1.06 (95% CI 0.87 to 1.30). No statistical heterogeneity was noticed (Chi² = 4.68, P = 0.91; I² = 0%). No significant subgroup differences were noticed between the four subgroups (PCA, PCN, PAN, and PAQ) (P = 0.37) (Analysis 2.2). Fourteen studies (n = 2284) reported data for patients discontinuing treatment due to adverse events. No significant difference was found between 10 days versus 7 days (2.8% versus 1.8%), with a RR of 1.18 (95% CI 0.67 to 2.06). No statistical heterogeneity was noticed (Chi² = 8.68, P = 0.65; I² = 0%), and no significant difference was noticed between the four subgroups (PCA, PCN, PAN, and PAQ) (P = 0.77) (Analysis 2.3).

days (15.9% versus 16.1%; RR 0.99, 95% CI 0.79 to 1.22) with no significant heterogeneity between studies (P = 0.98, I² = 0%) (Analysis 5.6). Eight studies (n = 1335) reported data for patients who discontinued treatment due to adverse events. There was no significant difference of the proportion of patients discontinuing due to adverse events between the two groups (RR 1.01, 95% CI 0.49 to 2.09; test for heterogeneity P = 0.42, I² = 0%) (Analysis 5.7). Most reported adverse events (≥ 3 studies) were of taste disturbance or glossitis (5 studies; RR 1.37, 95% CI 0.86 to 2.19) (Analysis 5.8), diarrhoea (5 studies; RR 0.92, 95% CI 0.60 to 1.42) (Analysis 5.9), nausea or vomiting (4 studies; RR 0.80, 95% CI 0.42 to 1.52) (Analysis 5.10), abdominal pain (3 studies; RR 1.41, 95% CI 0.72 to 2.74) (Analysis 5.11), and skin rash or pruritus (3 studies; RR 1.48, 95% CI 0.26 to 8.44) (Analysis 5.12). None of them showed significant difference between the two durations, and no significant heterogeneity was seen between the studies for all comparisons (test for heterogeneity P > 0.10, I² = 0% for all). Other reported adverse events included headache (2 studies; RR 1.53, 95% CI 0.77 to 3.03) (Analysis 5.13), dyspepsia or worsened dyspepsia (2 studies; RR 0.51, 95% CI 0.25 to 1.05) (Analysis 5.14), flatulence (1 study; RR 0.63, 95% CI 0.28 to 1.43) (Analysis 5.15), infection (1 study; RR 1.72, 95% CI 0.51 to 5.79) (Analysis 5.16), anorexia (1 study; RR 1.18, 95% CI 0.37 to 3.81) (Analysis 5.17), loss of appetite (1 study; RR 1.02, 95% CI 0.21 to 4.94) (Analysis 5.18), erythema (1 study; RR 0.33, 95% CI 0.01 to 8.03) (Analysis 5.19), and candidiasis (1 study; RR 1.32, 95% CI 0.05 to 31.66) (Analysis 5.20). No significant differences for other adverse events were shown between 10 and 7 days for all comparisons. Only one study reported serious adverse events, as defined by the authors, and no significant difference was shown between the two groups (Vakil 2004) (RR 1.31, 95% CI 0.30 to 5.79).

1.2.2. PCN triple therapy, 10 versus 7 days Only one of two studies in this group reported data for patients with adverse events and data of patients who discontinued treatment due to adverse events (Di Mario 2003a); The other study reported data for patients who discontinued treatment due to adverse events (Hurenkamp 2000). Both the proportion of patients with adverse events and the proportion of patients who discontinued treatment due to adverse events were not significantly different between the 10 and 7 days groups (25.5% versus 17.3%; RR 1.48, 95% CI 0.68 to 3.18 (Analysis 8.2), and 4.2% versus 1.3%; RR 3.32, 95% CI 0.36 to 30.82 (Analysis 8.3), respectively).

1.2.1. PCA triple therapy, 10 days versus 7 days Eight out of 17 studies in this group reported data for patients with adverse events, comprised of 1730 participants. The proportion of patients with adverse events was similar between 10 days and 7

1.2.3. PAN triple therapy, 10 versus 7 days One of four studies (Berrutti 2008) reported data for patients with adverse events. No significant difference was seen between 10 days


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versus 7 days (1.9% versus 0%), with a RR of 3.22 (95% CI 0.13 to 77.41) (Analysis 10.6). Three studies in this group reported data for patients who discontinued treatment with adverse events (Berrutti 2008; Filipec Kanizaj 2009; Pellicano 2002). No significant difference was found between 10 and 7 days (3.1% versus 1.7%; RR 1.45, 95% CI 0.41 to 5.18) without significant heterogeneity (P = 0.35, I² = 4%) (Analysis 10.7). Adverse events of nausea or vomiting were reported by two studies (Berrutti 2008; Filipec Kanizaj 2009) (RR 1.22, 95% CI 0.55 to 2.70) (Analysis 10.8). Adverse events that were reported by one study (Filipec Kanizaj 2009) included diarrhoea (RR 0.83, 95% CI 0.23 to 3.03) (Analysis 10.9), abdominal pain (RR 1.04, 95% CI 0.27 to 4.07) (Analysis 10.10), loss of appetite (RR 1.04, 95% CI 0.21 to 5.06) (Analysis 10.11), headache (RR 1.13, 95% CI 0.52 to 2.45) (Analysis 10.12), and taste disturbance (RR 1.04, 95% CI 0.40 to 2.69) (Analysis 10.12). None of these showed significant differences between the two duration groups.

1.2.4. PAQ triple therapy, 10 versus 7 days One of the two studies in this group reported data for patients with adverse events (Bago 2010). No significant difference between the two durations were found (20% versus 14.7%; RR 1.64, 95% CI 0.83 to 3.22) (Analysis 13.4). Both studies in this group reported data for patients discontinuing treatment due to adverse events (Bago 2010, Sacco 2010) (1.8% versus 1.7%), with a RR of 1.08 (95% CI 0.23 to 5.02) (Analysis 13.5). Adverse events reported by both studies included epigastric discomfort or abdominal pain (RR 1.27, 95% CI 0.35 to 4.63) (Analysis 13.6), nausea or vomiting (RR 1.22, 95% CI 0.42 to 3.57) (Analysis 13.7), diarrhoea (RR 1.44, 95% CI 0.46 to 4.46) (Analysis 13.8), and metallic taste or taste disturbance (RR 1.41, 95% CI 0.11 to 18.68) (Analysis 13.9). Adverse events reported by one study included constipation (Bago 2010) (RR 0.33, 95% CI 0.01 to 8.05) (Analysis 13.10), headache (Bago 2010) (RR 2.00, 95% CI 0.19 to 21.59) (Analysis 13.11), pruritus (Bago 2010) (RR 5.00, 95% CI 0.24 to 102.42) (Analysis 13.12), skin rash (Bago 2010) (RR 0.33, 95% CI 0.01 to 8.05) (Analysis 13.13), aphthous stomatitis (Sacco 2010) (RR 0.22, 95% CI 0.01 to 4.43) (Analysis 13.14), bloating (Sacco 2010) (RR 0.72, 95% CI 0.12 to 4.20) (Analysis 13.15), and loose stools (Sacco 2010) (RR 0.72, 95% CI 0.12 to 4.20) (Analysis 13.16). None of them showed significant difference between the two duration groups.

1.3. PPI triple therapy 14 days versus 10 days Five out of 12 studies reported data for patients with adverse events for the PPI triple therapy for 14 days or 10 days, with 789 participants. The pooled proportion of patients with adverse events was not significantly different for 14 days (23.8%) versus 10 days (22.9%), with a RR of 1.01 (95% CI 0.79 to 1.29). No statistical heterogeneity was noticed (P = 0.54, I² = 0%). No significant subgroup differences were noticed between the two subgroups (PCA, PAN) (P = 0.17) (Analysis 3.2). Seven studies reported data for patients who discontinued treatment due to adverse events for PPI triple therapy for 14 days versus 10 days, with 1215 participants. Pooled proportion of patients who discontinued treatment due to adverse events was not significantly different between 14 days (2.9%) and 10 days (3.1%), with a RR of 0.94 (95% CI 0.47 to 1.89). No statistical heterogeneity was noticed (P = 0.75, I² = 0%), nor any significant subgroup differences (PCA, PAN) (P = 0.86) (Analysis 3.3).

1.3.1 PCA 14 days versus 10 days Four out of 10 studies in this group reported data for patients with adverse events, with 675 participants (Cho 2001; Fennerty 1998; Laine 1996; Mantzaris 1999). Patients with adverse events were similar between 14 days and 10 days (26.7% versus 26.1%; RR 0.99, 95% CI 0.77 to 1.27) with no significant heterogeneity between studies (P = 0.76, I² = 0%) (Analysis 6.6). Five studies reported data for patients who discontinued treatment due to adverse events, with 820 participants (Fennerty 1998; Filipec Kanizaj 2009; Karatapanis 2011; Laine 1996; Park 2009a). There was a similar discontinuation rate between the two groups (2.7% vs 3.1%; RR 0.89; 95% CI 0.36 to 2.20; test for heterogeneity P = 0.37, I² = 4%) (Analysis 6.7). Individual adverse events included nausea or vomiting (2 studies; RR 1.36, 95% CI 0.52 to 3.58) (Analysis 6.8); diarrhoea (2 studies; RR 0.87, 95% CI 0.33 to 2.25) (Analysis 6.9); taste disturbance or glossitis (2 studies; RR 1.05, 95% CI 0.45 to 2.42) (Analysis 6.10); headache (1 study; RR 1.55, 95% CI 0.36 to 6.71) (Analysis 6.11); loss of appetite (1 study; RR 0.69, 95% CI 0.07 to 6.49) (Analysis 6.12); abdominal pain (1 study; RR 1.38, 95% CI 0.24 to 8.03) (Analysis 6.13); and skin rash or itching (1 study; RR 1.98, 95% CI 0.18 to 21.40) (Analysis 6.14). No significant differences in these adverse events were seen between the two durations.

1.3.2 PAN 14 days versus 10 days

1.2.5. PANi triple therapy, 10 versus 7 days The only study in this group did not report adverse event data for PPI + amoxicillin + a nitrofuran 10 days versus 7 days (Lv 2011).

One of four studies in this group reported data for patients with adverse events, with 114 participants (Berrutti 2008). Proportion of patients with adverse events was not significantly different between 14 days and 10 days (8.2% versus 1.9%; RR 4.34, 95% CI 0.52 to 36.02) (Analysis 11.6).


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Three studies in this group reported data for patients who discontinued treatment due to adverse events (395 participants) (Berrutti 2008; Filipec Kanizaj 2009; Pellicano 2002). Similar proportions of patients discontinued treatment due to adverse events in the 14 and 10 days groups (3.5% versus 3.1%), without a significant difference between the two groups (RR 1.02, 95% CI 0.33 to 3.15). No significant heterogeneity was seen (P = 0.85, I² = 0%) (Analysis 11.7). Individual adverse events included diarrhoea (2 studies; RR 1.45, 95% CI 0.32 to 6.52) (Analysis 11.8); dysgeusia or taste disturbance (2 studies; RR 0.1.78, 95% CI 0.63 to 5.04) (Analysis 11.9); nausea or vomiting (2 studies; RR 0.66, 95% CI 0.23 to 1.89) (Analysis 11.10); headache (2 studies; RR 1.09, 95% CI 0.45 to 2.65) (Analysis 11.11); loss of appetite (1 study; RR 1.34, 95% CI 0.23 to 7.83) (Analysis 11.12); and abdominal pain (1 study; RR 1.51, 95% CI 0.35 to 6.54) (Analysis 11.13). No significant differences in these adverse events were seen between the two durations. 2. PPI + Bismuth + two antibiotics quadruple therapy

Six studies provided data for PPI + bismuth + two antibiotics quadruple therapy. 2.1 PPI bismuth quadruple therapy 14 days versus 7 days Two of three studies in this group reported data for patients with adverse events (316 participants) (Daghaghzadeh 2007; Sun 2010). The proportion of patients with adverse event was not significantly different between the 14 days and 7 days groups (15.8% versus 13.9%; RR 1.13, 95% CI 0.67 to 1.92) (Analysis 14.5). However, patients discontinuing treatment due to adverse events was significantly different between the 14 days and 7 days groups (2 studies, 7.0% versus 0.6%; RR 7.48, 95% CI 1.38 to 40.63; P = 0.02) (Analysis 14.6). The NNTH was 24 (95% CI 4 to 417). Individual adverse events included diarrhoea (2 studies; RR 1.38, 95% CI 0.54 to 3.56) (Analysis 14.7); skin rash and itching (2 studies; RR 0.43, 95% CI 0.06 to 2.91) (Analysis 14.8); dizziness and drowsiness (2 studies; RR 1.12, 95% CI 0.44 to 2.84) (Analysis 14.9); abdominal discomfort (1 study; RR 0.75, 95% CI 0.17 to 3.24) (Analysis 14.10); fever (1 study; RR 3.00, 95% CI 0.12 to 72.53) (Analysis 14.11); vomiting (1 study; RR 0.50, 95% CI 0.05 to 5.40) (Analysis 14.12); fatigue (1 study; RR 1.00, 95% CI 0.06 to 15.71) (Analysis 14.13); headache (1 study; RR 7.00, 95% CI 0.88 to 55.57) (Analysis 14.14), and nausea (1 study; RR 1.67, 95% CI 0.64 to 4.36) (Analysis 14.15). No significant differences in these adverse events were seen between the two durations.

discontinued treatment due to adverse events (Zheng 2009). There was no significant difference between the 10 days and 7 days groups (2.2% versus 2.3%; RR 0.96, 95% CI 0.06 to 14.80) (Analysis 15.4). 2.3 PPI bismuth quadruple therapy 14 days versus 10 days One study provided data for PPI bismuth quadruple therapy for 14 days or 10 days (n = 417) (Dore 2011). Patients with adverse events (15.8% versus 10.2%) and patients who discontinued treatment due to adverse events (2.0% versus 1.4%) were not significantly different between the 14 days and 10 days groups (RR 1.55, 95% CI 0.93 to 2.57; and RR 1.42, 95% CI 0.32 to 6.26, respectively) (Analysis 16.2; Analysis 16.3). Reported individual adverse events included nausea (RR 1.49, 95% CI 0.68 to 3.28) (Analysis 16.4), vomiting (RR 7.45, 95% CI 0.39 to 143.30) (Analysis 16.5), stomach ache (RR 1.06, 95% CI 0.38 to 2.98) (Analysis 16.6), diarrhoea (RR 0.64, 95% CI 0.15 to 2.64) (Analysis 16.7), glossitis (RR 5.32, 95% CI 0.26 to 110.15) (Analysis 16.8), vaginitis (RR 3.19, 95% CI 0.13 to 77.91) (Analysis 16.9), dysphagia (RR 3.19, 95% CI 0.13 to 77.91) (Analysis 16.10), dizziness (RR 0.35, 95% CI 0.01 to 8.66) (Analysis 16.11), patient-reported unfitness or discomfort (RR 2.37, 95% CI 1.40 to 3.99) (Analysis 16.12), and patient-reported fatigue and weakness (RR 1.70, 95% CI 1.01 to 2.88) (Analysis 16.13). The sensitivity analyses OR was 0.07 (95% CI 0.00 to 0.13, P = 0.04) and fixed-effect model RR 1.84 (95% CI 1.01 to 3.33). No significant differences in these adverse events were seen between the two durations, except patients who reported unfitness or discomfort (19.8% versus 8.4%; NNTH 9, 95% CI 4to 30) and patient-reported fatigue and weakness were significantly increased with 14 days (15.8% versus 9.3%), with a NNTH of 15 (95% CI 6 to 1378). 3. PPI + three antibiotics quadruple therapy

One study provided data for PPI + three antibiotics quadruple therapy and the duration investigated was 10 days versus 7 days (n = 180) (Basu 2011). The proportion of patients discontinuing treatment due to adverse events was reported. No significant difference was seen between 10 days and 7 days (5.6% versus 3.3%; RR 1.67, 95% CI 0.41 to 6.77) (Analysis 17.2). 4. PPI + one antibiotic dual therapy

Two studies provided data for PPI dual therapy and compared H. pylori eradication for 14 days versus 7 days (Chew 1994) and 10 days versus 7 days (Di Caro 2002a), respectively. 4.1 PPI dural therapy 14 days versus 7 days

2.2 PPI bismuth quadruple therapy 10 days versus 7 days Two studies provided data for PPI bismuth quadruple therapy for 10 days or 7 days. One study provided data for patients who

One study reported data for high dose PPI (omeprazole 60 mg bid) plus clarithromycin (500 mg bid) for 14 days versus 7 days (n = 64) (Chew 1994). The proportion of patients with adverse events was


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significantly increased with 14 days (32.3% versus 9.1%), with a RR of 3.55 (95% CI 1.08 to 11.70; NNTH 4, 95% CI 1 to 145) (Analysis 18.2). 4.2 PPI dual therapy 10 days versus 7 days One study reported data for rabeprazole (20 mg od) plus levofloxacin (500 mg od) for 10 days versus 7 days (n = 80) (Di Caro 2002a). Patients with adverse events (15% versus 0%) were not significantly different between 10 days and 7 days (RR 13.00, 95% CI 0.76 to 223.33) (Analysis 19.2), and no patient discontinued treatment due to adverse events.

durations (5.5% versus 1.8%; RR 3.00, 95% CI 0.32 to 27.96) (Analysis 21.3). Individual adverse events were reported by one study (Savarino 1999), and included epigastric pain (RR 1.67, 95% CI 0.42 to 6.64) (Analysis 21.4), nausea (RR 1.00, 95% CI 0.26 to 3.80) (Analysis 21.5), diarrhoea (RR 1.50, 95% CI 0.26 to 8.63) (Analysis 21.6), vomiting (RR 3.00, 95% CI 0.32 to 27.96) (Analysis 21.7), headache (RR 1.00, 95% CI 0.15 to 6.85) (Analysis 21.8), skin rash (RR 1.00, 95% CI 0.06 to 15.59) (Analysis 21.9), and taste disturbance (RR 1.25, 95% CI 0.35 to 4.41) (Analysis 21.10). No significant differences in these adverse events were seen between the two durations.

5. H2 RA + bismuth-based quadruple therapy

Three studies reported data for H2 RA bismuth quadruple therapy. One was H2 RA + bismuth + two antibiotics for 14 versus 7 days (Kaviani 2001), and two were RBC + two antibiotics for 10 versus 7 days (Knigge 1999; Savarino 1999). 5.1 H2 RA + bismuth + two antibiotics quadruple therapy 14 versus 7 days One study reported data for ranitidine 300 mg bid, bismuth subcitrate 240 mg bid, amoxicillin 1 g bid and metronidazole 500 mg bid for 14 versus 7 days (n = 160) (Kaviani 2001). The proportion of patients who discontinued treatment due to adverse events was not significantly different between 14 days and 7 days (1.3% versus 0%; RR 3.00, 95% CI 0.12 to 72.56) (Analysis 20.2). Individual adverse events included anorexia (RR 0.85, 95% CI 0.37 to 1.95) (Analysis 20.3), nausea (RR 1.57, 95% CI 0.60 to 4.07) (Analysis 20.4), vomiting (RR 0.94, 95% CI 0.06 to 14.73) (Analysis 20.5), diarrhoea (RR 0.78, 95% CI 0.25 to 2.44) (Analysis 20.6), constipation (RR 0.38, 95% CI 0.08 to 1.87) (Analysis 20.7), dizziness (RR 0.71, 95% CI 0.32 to 1.56) (Analysis 20.8), headache (RR 1.06, 95% CI 0.44 to 2.58) (Analysis 20.9), fatigue (RR 0.61, 95% CI 0.33 to 1.12) (Analysis 20.10), unpleasant tastes (RR 1.22, 95% CI 0.84 to 1.76) (Analysis 20.11), dry mouth (RR 1.05, 95% CI 0.69 to 1.60) (Analysis 20.12), anal itching (RR 4.71, 95% CI 0.23 to 96.27) (Analysis 20.13), dysuria (RR 0.63, 95% CI 0.19 to 2.12) (Analysis 20.14), and urticaria (RR 0.31, 95% CI 0.03 to 2.94) (Analysis 20.15). No significant differences in these adverse events were seen between the two durations. 5.2 RBC + two antibiotics 10 versus 7 days Two studies (n = 215) reported data for RBC 400 mg bid plus two antibiotics (metronidazole 500 mg plus tetracycline 500 mg bid, and metronidazole 500 mg bid plus clarithromycin 250 mg bid, respectively) (Knigge 1999; Savarino 1999). The proportion of patients with adverse events was non-significantly different between 14 days and 7 days (2 studies, 37.7% versus 34.9%; RR 1.07, 95% CI 0.78 to 1.46) (Analysis 21.2). The proportion of patients who discontinued treatment was reported by one study (Savarino 1999), which was also not significantly different between the two

6. H2 RA bismuth triple therapy

H2 RA bismuth triple therapy 14 days versus 7 day Two studies provided data for H2 RA bismuth triple therapy (RBC 400 mg bid plus clarithromycin 500 mg bid) for 14 days versus 7 days (n = 232) (Mesquita 2005; Pozzato 1998). Both studies in this group reported patients with adverse events and patients who discontinued treatment due to adverse events (Mesquita 2005; Pozzato 1998). Both were not significantly different between 14 and 7 days (4.6% versus 7.1%; RR 0.68, 95% CI 0.23 to 2.02 (Analysis 22.2), and 0% versus 0.9%; RR 0.33, 95 % CI 0.01 to 8.01 (Analysis 22.3), respectively). Only one study reported individual adverse events (Pozzato 1998). Reported adverse events included nausea (RR 0.33, 95% CI 0.01 to 8.01) (Analysis 22.4), headache (RR 0.33, 95% CI 0.01 to 8.01) (Analysis 22.5), pruritus (RR 3.00, 95% CI 0.12 to 72.10) (Analysis 22.6), allergic dermatitis (RR 0.33, 95% CI 0.01 to 8.01) (Analysis 22.7), conjunctivitis (RR 0.33, 95% CI 0.01 to 8.01) (Analysis 22.8), and asthenia (RR 0.33, 95% CI 0.01 to 8.01) (Analysis 22.9). None of the adverse events were significantly different between 14 and 7 days.

7. H2 RA triple therapy (H2 RA + two antibiotics)

H2 RA triple therapy (H2 RA + two antibiotics) 14 days versus 7 days Three studies reported data for H2 RA triple therapy regimens of 14 versus 7 days (n = 417). Regimens were famotidine 20 mg bid, amoxicillin 1 g bid, and metronidazole 400 mg bid (Hu 2003); famotidine 40 mg bid, amoxicillin 1 g bid, and tinidazole 500 mg bid (Hsu 2005); and lafutidine 20 mg bid, clarithromycin 500 mg bid, and amoxicillin 1000 mg bid (Kim 2008). The proportion of patients with adverse events was reported by two studies (Hsu 2005; Kim 2008). No significant difference of the proportion of patients with adverse event was seen between the 14 days and 7 days groups (12.8% versus 9.7%; RR 1.32, 95% CI 0.72 to


41

2.41) (Analysis 23.6). The proportion of patients who discontinued treatment due to adverse events (Hsu 2005; Hu 2003; Kim 2008) was also not significant different between the two durations (0% versus 0.5%; RR 0.32, 95% CI 0.01 to 7.83) (Analysis 23.7). Reported individual adverse event included diarrhoea (2 studies; RR 1.74, 95% CI 0.81 to 3.71) (Analysis 23.8); nausea or vomiting (2 studies; RR 2.85, 95% CI 0.91 to 8.90) (Analysis 23.9); headache (1 study; RR 0.33, 95% CI 0.01 to 8.02) (Analysis 23.10); taste alteration (1 study; RR 1.00, 95% CI 0.06 to 15.62) (Analysis 23.11); epigastric discomfort (1 study; RR 0.97, 95% CI 0.06 to 15.27) (Analysis 23.12); and dizziness (1 study; RR 2.90, 95% CI 0.12 to 70.47) (Analysis 23.13). None were significantly different between 14 and 7 days.

8. Bismuth triple therapy (bismuth salt + two antibiotics)

Bismuth triple therapy (bismuth salt + two antibiotics) 14 days versus 7 days Two studies reported data for 14 days versus 7 days (n = 141). The regimens were BSS 250 mg bid, tetracycline 500 mg bid, and metronidazole 250 mg bid (Muszynki 1992); and CBS 120 mg bid, tetracycline 500 mg bid, and metronidazole 500 mg tid for 14

or 7 days (de Boer 1994). Patients with adverse events or discontinuation of treatment due to adverse events were not significantly different between 14 and 7 days although there was a trend favouring 7 days (78.4% versus 70.1%; RR 1.10, 95% CI 0.93 to 1.29, and 10.8% versus 2.6%; RR 2.86, 95% CI 0.71 to 11.51, respectively) (Analysis 24.2; Analysis 24.3). Nausea (RR 1.26, 95% CI 0.86 to 1.86) (Analysis 24.4), vomiting (RR 2.11, 95% CI 0.71 to 6.27) (Analysis 24.5), and metallic taste or bad taste (RR 1.00, 95% CI 0.71 to 1.40) (Analysis 24.6) were reported by both studies. Other reported adverse events included heartburn (1 study; RR 5.00, 95% CI 0.25 to 98.27) (Analysis 24.7), diarrhoea (RR 0.90, 95% CI 0.60 to 1.36) (Analysis 24.8), stomach pain (RR 0.18, 95% CI 0.04 to 0.75) (Analysis 24.9), burning sensation in the oesophagus (RR 3.00, 95% CI 0.13 to 69.70) (Analysis 24.10), burning sensation in the mouth (RR 3.00, 95% CI 0.13 to 69.70) (Analysis 24.11), dysphagia (RR 3.00, 95% CI 0.13 to 69.70) (Analysis 24.12), burping (RR 0.32, 95% CI 0.01 to 8.26) (Analysis 24.13), anorexia (RR 1.58, 95% CI 0.78 to 3.21) (Analysis 24.14), and dizziness (RR 0.96, 95% CI 0.44 to 2.07) (Analysis 24.15). None of the adverse events were significantly different between 14 and 7 days; except stomach pain which was significantly decreased in the 14 days group (4% versus 22%), reported in one study (de Boer 1994) (Analysis 24.9).


42


A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]



Assumed risk

Corresponding risk

7 days treatment


H. pylori persistence, re- Moderate gardless of regimen and 26 per 100 dose

H. pylori persistence, Moderate PCA subgroup 26 per 100

H. pylori persistence, Moderate PCN subgroup 18 per 100

H. pylori persistence, Moderate PAN subgroup 26 per 100




Comments

RR 0.8 (0.72 to 0.89)

4628 (24 studies)


NNT 21 (95% CI 5 to 38)

RR 0.8 (0.7 to 0.91)

3271 (17 studies)


NNT 21 (95% CI 14, 48)

RR 0.99 (0.55 to 1.79)

148 (2 studies)

⊕

very low4,5,6

RR 0.85 (0.65 to 1.12)

573 (4 studies)

⊕⊕

low2,6,7,8

20 per 100 (18 to 23)

20 per 100 (18 to 23)

18 per 100 (10 to 33)

22 per 100 (17 to 29)

43


H. pylori persistence, Moderate PAQ subgroup 22 per 100

H. pylori persistence, Moderate PANi subgroup 26 per 100


RR 0.58 (0.36 to 0.95)

346 (2 studies)

⊕⊕

low6,9,10

RR 0.79 (0.52 to 1.2)

290 (1 study)

⊕

very low6,11,12

RR 1.06 (0.87 to 1.3)

2089 (11 studies)

⊕⊕⊕ moderate1,2

NNT 7 (95% CI 5to 59)

13 per 100 (8 to 21)

21 per 100 (14 to 31)

16 per 100 (13 to 19)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; NNT: number needed to treat GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1

44

Most information is obtained from studies with high risk or unclear risk of bias. Especially, most studies were not blinded for performance or outcome assessment. Open label studies ay lead to bias in adverse event reporting, different compliance, and medications out of study regimens. However, the assessment for H. pylori eradication as an objective outcome is less likely to be impacted by the open-label design compared to adverse events. 2 There is no significant heterogeneity among studies. 3 The overview of the funnel plot and results of the tests for funnel plot asymmetry indicated that there was no evidence of publication bias or other small-study effects for this comparison 4 One study was considered high risk of bias for blinding of participants and personnel, and the other study was considered as a unclear risk of bias study 5 Only two studies were eligible for this comparison, total sample size was very small. Although no significant treatment effect is shown, 95% confidence interval around the pooled estimate of effect includes both 1) no effect and 2) appreciable benefit or appreciable harm. Further research is likely to change the estimate. 6 Fewer than ten studies were included in this comparison, therefore, no test for funnel plot asymmetry was performed. 7 Two studies were considered as high risk of bias and two studies were considered as unclear risk of bias.


8

Only four studies were eligible for this comparison. Although no significant treatment effect is shown, 95% confidence interval around the pooled estimate of effect includes both 1) no effect and 2) appreciable benefit. further research is likely to change the estimate. 9 Both studies were considered as high risk of bias due to high risk of blinding of participants and personnel. 10 Only two studies were eligible for this comparison, total sample size was small. Although significant treatment effect is shown, further research is likely to change the estimate. 11 As the only study in this comparison, this study was considered as unclear risk of bias 12 Only one study was eligible for this comparison, total sample size was small. Although no significant treatment effect is shown, 95% confidence interval around the pooled estimate of effect includes both 1) no effect and 2) appreciable benefit. Further research is likely to change the estimate.

xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx

45




Assumed risk

Corresponding risk

10 days treatment


H.pylori persistence, re- Moderate gardless of regimen and 21 per 100 dose

H.pylori persistence, Moderate PCA subgroup 20 per 100

H.pylori persistence, Moderate PAN subgroup 26 per 100





Comments

RR 0.72 (0.58 to 0.9)

2111 (12 studies)


NNT 17 (95% 11 to 46)

RR 0.69 (0.52 to 0.91)

1596 (10 studies)


NNT 16 (95% CI 10 to 54)

RR 0.79 (0.54 to 1.15)

515 (4 studies)

⊕⊕

low2,6,7,8

RR 1.01 (0.79 to 1.29)

789 (5 studies)

⊕⊕

low1,2,8,9

15 per 100 (12 to 19)

14 per 100 (10 to 18)

21 per 100 (14 to 30)

19 per 100 (15 to 24)

46


*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; NNT: number needed to treat GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1

Most information is obtained from studies with high risk or unclear risk of bias. Especially, most studies were not blinded for performance or outcome assessment. Open label studies ay lead to bias in adverse event reporting, different compliance, and medications out of study regimens. However, the assessment for H. pylori eradication as an objective outcome is less likely to be impacted by the open-label design compared to adverse events. 2 There is no significant heterogeneity among studies. 3 The overview of the funnel plot and results of the tests for funnel plot asymmetry indicated that there might be evidence for publication bias or other small-study effects, only when studies were analyzed separated by the regimens used (12 studies 14 comparisons). When the different regimens from the same studies were combined (12 studies 12 comparisons), no significant publication bias or other smallstudy effect was seen. We can not rule out that the tests might be false positive or false negative results, the clinical importance of publication bias or small-study effects si likely to be very small. Therefore, the quality of evidence is not downgraded for publication bias. 4 There is moderate by significant heterogeneity among studies. However, the heterogeneity can be explained by geographic location and baseline disease. Subgroup analyses and sensitivity analyses suggest prolonged treatment duration increase H. pylori eradication. Therefore, the quality of evidence is not downgraded for inconsistency/heterogeneity. 5 The overview of the funnel plot and results of the tests for funnel plot asymmetry indicated that there was no evidence of publication bias or other small-study effects for this comparison 6 Only four studies were eligible in this comparison. One study was considered as high risk of bias for selective reporting and one study was considered as high risk for blinding of participants and personnel. Two other studies were considered unclear risk of bias. 7 Only four studies provided data for this comparison. Although no significant benefit is shown, 95% confidence interval around the pooled estimate of effect includes both 1) no effect and 2) appreciable benefit. Further research is likely to change the estimate. 8 Fewer than ten studies were included in this comparison, therefore, no test for funnel plot asymmetry was performed. 9 Only five studies provided data for this comparison. Although no significant harm is shown, 95% confidence interval around the pooled estimate of effect includes both 1) no effect and 2) appreciable harm. Further research is likely to change the estimate.

47

DISCUSSION H. pylori is recognized as an etiological factor in the pathogenesis of several gastrointestinal (GI) diseases including peptic ulcer (PUD) and gastric cancer. H. pylori eradication is the recommended therapy for PUD (Malfertheiner 2012a) because H. pylori infection was originally identified as the main cause of PUD; and approximately 90% to 95% of duodenal ulcers and 60% to 80% of gastric ulcers are associated with H. pylori (Hunt 1996). A one to two week course of eradication therapy is an effective treatment for H. pylori positive PUD (Ford 2006); the management of PUD has improved substantially following the introduction of PPIs and therapy for H. pylori eradication (Sung 2009). In addition, an H. pylori test and eradication are recommended in several other gastrointestinal (GI) diseases (Malfertheiner 2007; Malfertheiner 2012a; Malfertheiner 2012b). Currently, the treatment success rate of first line PPI triple therapy fails to reach 80% in the majority of studies worldwide (Graham 2010). This might be improved by increasing duration of therapy (De Francesco 2004) but the optimal duration for H. pylori eradication is still controversial, despite many guidelines and several systematic reviews.

Summary of main results Seventy-five studies provided data for H. pylori eradication, comparing 7 days, 10 days, or 14 days treatment duration. Reported regimens included PPI + two antibiotics triple therapy (n = 59), PPI bismuth-based quadruple therapy (n = 6), PPI + three antibiotics quadruple therapy (n = 1), PPI dual therapy (n = 2), H2 RA bismuth quadruple therapy (n = 3), H2 RA bismuth-based triple therapy (n = 2), H2 RA + two antibiotics triple therapy (n = 3), and bismuth + two antibiotics triple therapy (n = 2). PPI triple therapy In this study, we systematically reviewed all published H. pylori eradication regimens with data available to compare the efficacy and safety of three different treatment durations. Although more than 100 different regimens for H. pylori are reported (Freston 1997), most guidelines recommend PPI triple therapy as first line therapy and favour PCA and PCN regimens (Malfertheiner 2012a). It is understandable, therefore, that the most commonly evaluated H. pylori eradication regimens are PPI-based triple therapies comprising a PPI plus two antibiotics (59 studies, 90 eligible comparisons, five types of regimen), providing us the most robust data for this topic. Of the eligible studies, PCA is the most commonly used PPI-based triple therapy, followed by PAN, PCN, PAQ, and then PANi. Our results suggest that, regardless of the type and dose of antibiotics, increased duration of PPI triple therapy from 7 to 14 days significantly increases the H. pylori eradication rate, with a NNT of 11. Significantly increased eradication rates were also seen for PPI triple therapy with 10 versus 7 days, with a NNT of 21; and 14 versus 10 days, with a NNT of 17;

although fewer studies provided data for the last finding compared with 14 days versus 7 days. For PCA and PAN triple therapy, significantly increased efficacy was seen with 14 versus 7 days, with NNTs of 12 and 11, respectively. Significantly increased eradication rates were also seen for PCA with 10 versus 7 days (NNT 21) and 14 versus 10 day (NNT 16). These data suggest that for PCA and PAN, increased duration from 7 days to 14 days is associated with a significantly increased H. pylori eradication rate. In addition, for PCA increased duration from 7 days to 10 days as well as from 10 days to 14 days also significantly increases the H. pylori eradication rate. A trend towards increased H. pylori eradication rates was seen for the increased duration of PAN, for 10 versus 7 days and 14 versus 10 days. There were less data for PCN with a trend towards increased efficacy for 14 versus 7 days and 10 versus 7 days, although this was not statistically significant (Table 1). The limited number of studies for each of these comparisons suggest the results are not robust, and more studies are needed to confirm the benefit of increased duration for PCN triple therapy. However, increased antibiotic resistance has been seen with metronidazole or clarithromycin, especially after previous treatment failure (Pilotto 2000), and many new antibiotics and new regimens (for example, sequential therapy or non-bismuth quadruple (concomitant) or hybrid therapies are being investigated for increased H. pylori eradication efficacy compared to PPI-based triple therapy, and have shown promising efficacy (Gatta 2009; Gatta 2013; Gisbert 2011; Greenberg 2011; Moayyedi 2009; Zullo 2013). As a result, it is unlikely that there will be many future trials to confirm the benefit of an increased duration of PCN. Limited data for PAQ suggest increased duration from 7 days to 14 days and 7 days to 10 days significantly increased the H. pylori eradication rate, with only two studies for each duration comparison (Bago 2010; Bosques-Padilla 2004; Ercin 2010; Sacco 2010). The studied quinolones were ofloxacin, levofloxacin, and moxifloxacin. Although a significantly increased H. pylori eradication was seen with 14 versus 7 days (NNT 3) and with 10 versus 7 days (NNT 7), more studies are needed for this regimen to confirm these results. Only one study compared PANi for 7 days versus 10 days, and no significant difference was seen between the durations. Adverse events were the secondary outcome in many of the trials and it was considered as the secondary outcome in our meta-analysis. However, it is common for one patient to report several side effects in a trial. Some studies only provided numbers of individual adverse events, therefore the percentage of total adverse event can be greater than 100% if we simply add up the event numbers and divide the sum by the total sample size. In some trials, we could not retrieve adverse event data reported other than as participant numbers for each event, or the percentage of participants for each event, therefore the useful information was less than we expected. In addition, some studies reported adverse events in the ITT sample, therefore the true drug-related adverse event may be


48

underreported. On the other hand, some studies reported adverse events in the PP sample, therefore the adverse events maybe also be underreported if patients dropped out due to adverse events. More importantly, the terminologies and definitions used to represent safety vary in primary studies; the quality and quantity of assessing and reporting of adverse events is largely inadequate in RCTs (Ioannidis 2004). As a result, most meta-analyses are unable to provide a comprehensive analysis of adverse events (Golder 2006) and this report is not an exception. As commented by Fuccio et al in their meta-analysis, “Incomplete and often inadequate data on the frequency, severity, and type of adverse events that occurred during the various treatment periods prevent any definitive conclusion on the tolerability of the different therapy durations” (Fuccio 2007). In this systematic review, the overall proportion of patients reporting drug-related adverse events during PPI-based triple therapy was less than 30%, with the pooled proportion ranging from approximately 15% to 16% for 7 days, 16% to 23% for 10 days, and 19% to 24% for 14 days. The pooled proportion of patients who discontinued treatment due to adverse events were fewer than 10%, approximately 2% for 7 days, approximately 3% for 10 days, and 2% to 3% for 14 days of PPI triple therapy. Most reported adverse events are similar to those reported in other clinical trials for individual antibiotics, such as diarrhoea, taste disturbance, skin rash, dyspepsia, nausea, headache, etc. No significant difference in overall adverse events was seen between durations for PPIbased triple therapy, except a marginally significant difference between 14 days and 7 days for PCA (NNTH 30). As for individual adverse symptoms, significant increases in taste disturbance, metallic taste or glossitis, and nausea or vomiting were seen with 14 days PCA triple therapy compared with 7 days, with NNTHs of 47 and 57, respectively. Although none of the eight individual studies reported a significant difference in the adverse events, most reported that adverse events were mild; and the authors seldom separated the adverse events into drug-related and not drugrelated. Considering the limited number of eligible studies and that more adverse events were seen with longer durations in most of the comparisons, we cannot exclude that the non-significant difference in adverse events observed was due to the lack of power in these comparisons. The current results from PPI triple therapy suggest that increasing the treatment duration from 7 to 10 days, 10 to 14 days, or from 7 to 14 days significantly increases the H. pylori eradication rate without substantially increasing adverse events. In other words, increasing the length of PPI triple therapy beyond 7 days improves treatment efficacy, and the optimal duration is 14 days between the three choices. The ITT eradication rate should reach at least 90% to be considered as acceptable for a regimen (Graham 2010). However, in our meta-analysis, the unweighted pooled eradication rate was less than 85% for commonly reported triple regimens for 14 days (81.9% to 84.4%); and the unweighted pooled rate was lower for 10 days (78.5% to 79.9%) and 7 days (73% to

76%). In addition, a high eradication rate from these clinical trials might not be translated as a similarly high eradication rate in future studies or in the real world. For instance, a Greek study examined the cumulative H. pylori eradication rates by adopting first (omeprazole, clarithromycin and amoxycillin) and second line regimens (omeprazole, bismuth, metronidazole and tetracycline quadruple therapy) as proposed by the Maastricht III consensus and a third line empirical levofloxacin-based regimen. All regimens were used for 10 days and the eradication rates (ITT analysis) were only 70.3%, 69.1%, and 70%, respectively; although the total eradication added up to 89.6% (Rokkas 2009). The first line eradication rate at 10 days in this study (70.3%) was lower than the eradication rate in our PCA arms (78.5% to 79.9%). Evidence suggests that eradication rates are at the lowest levels seen in the past decade, and are likely to fall further because of the increasing prevalence of antimicrobial resistance worldwide (Vakil 2009). Therefore, even if the duration of PPI triple therapy is increased, the improved H. pylori eradication efficacy in the real world might not be as good as expected. Due to the limited information of the included studies, we are not able to answer some other clinical important questions, such as, whether the treatment effects between different durations are different for different PPIs and antibiotics or different doses, pre-treatment antibiotic resistance versus susceptible strains, with or without pre- or post-eradication PPIs, different baseline diseases, and type or combination of H. pylori diagnostic or assessing method. In theory, lower dose PPIs and antibiotics are associated with lower H. pylori eradication rates compared to those of standard dose regimens, but the impact on the comparison between durations is unclear. Omeprazole dose was suggested as one of the significant factors in meta-regression of omeprazole-based eradication regimens (Schmid 1999). It is known that PPI-based triple therapies containing a single dose of PPI are less effective than regimens containing a standard double dose of PPI, but this beneficial effect was restricted to the PCA rather than PCN regimen (Vallve 2002). An earlier meta-analysis of 15 RCTs also showed that double-dose PPI therapy is optimal in PCA regimens, with a NNT of 18, but not in PCN regimens, although the sample size was small for the latter group (Ford 2003). A more recent meta-analysis compared 7 days high-dose versus standard-dose PPI triple therapy (clarithromycin and either amoxicillin or metronidazole) and the results suggested that H. pylori eradication therapy was increased with high-dose triple therapy (82% versus 74%, respectively) (Villoria 2008). Controversies were also raised as there were poor eradication rates in both regimens, therefore the improvements by increasing the dose of PPIs are unlikely to be clinically significant, especially considering that the prevalence of clarithromycin resistance in most of the world is increasing (Sugimoto 2009). No evidence so far suggests that higher-dose PPI triple therapy shows a bigger treatment effect between different durations compared to standard or lowdose PPI therapy. Meta-analysis suggested that the higher dose of


49

clarithromycin (500 mg bid versus 250 mg bid) was optimal for 7 days PCA but high and low-dose clarithromycin were equally effective for PCN regimens (Huang 1999); the optimum clarithromycin dose in a PCA regimen was 500 mg bid but was 250 mg bid in PCN (Ford 2003). Although we performed subgroup analyses based on the regimens (dose of PPIs or antibiotics) for PPI triple therapy regimens that showed significant differences between two durations and had non-standard dose subgroups (for example, PCA 14 days versus 7 days, PCA 10 days versus 7 days, PCA 14 days versus 10 days, and PAN 14 days versus 7 days), significant differences were sustained in all subgroups of standard doses (except PAN 14 days versus 7 days) but not in all of the low doses or high doses or unclear PPI doses subgroups (Analysis 4.1; Analysis 5.1; Analysis 6.1; Analysis 9.1). No significant subgroup difference was found between the regimen subgroups. However, these non-standard dose PPI or antibiotic subgroups have only one to four studies in each subgroup, and the trend still favoured longer duration therapy. Therefore, it cannot be excluded that the non-significant difference between the two durations within these non-standard dose subgroups were due to the lack of power to detect a significant difference. Although we do not have further evidence of the impact on treatment duration efficacy, standard doses of PPIs and antibiotics should be used in daily practice to minimize the subsequent development of bacterial resistance and to avoid low eradication rates within first line therapy. Studies have shown that pre-treatment resistance to clarithromycin and metronidazole (Dore 2000) and lack of adherence to treatment are the main predictors of treatment failure (Fuccio 2008); and that clarithromycin resistance predicts eradication failure “almost perfectly” (Broutet 2003). Clarithromycin is one of the most useful antimicrobials against H. pylori as it concentrates in the gastric mucosa and has a bactericidal effect on H. pylori. It is also an acidstable macrolide with a broad spectrum of antibacterial activity, and its effect is potentiated by acid inhibition with mild side effects (Leung 2000). Amoxicillin also has a bactericidal effect on H. pylori but it is less effective in the stationary growth phase and cell-adherent on slowly growing H. pylori. Amoxicillin is fairly acid stable with enhanced activity when used with PPIs (Hirschl 1996). For triple therapy, clarithromycin resistance had a greater effect on the effectiveness of treatment than nitroimidazole resistance; efficacy was further reduced in the presence of dual resistance (Fischbach 2007). Evidence also suggests that nitroimidazole-based regimens were less successful in populations with frequent childhood H. pylori infection or metronidazole resistance, but more successful in northeastern Asia. Non-nitroimidazole based regimens of longer duration and those from early years were most successful (Fischbach 2002). Clarithromycin-based triple regimens (PCA or PCN) are still considered the effective triple therapy for H. pylori eradication and are therefore the most recommended treatment worldwide (Gisbert 2007). Just as is shown in our metaanalysis, PCA is more commonly used than PCN or PAN due to the significantly increased and higher resistance to metronidazole

compared to clarithromycin and amoxicillin (De Francesco 2010; Larsen 2012), especially in the regions where resistance of H. pylori against metronidazole is high. A PCN triple regimen is more successful than PCA in susceptible strains but not in cases of metronidazole resistance; both PCA and PCN are the recommended first choice regimens in populations with less than 15% to 20% clarithromycin resistance, and a PAN triple regimen is recommended as a possible second choice treatment, as suggested by the Maastricht III Consensus (Malfertheiner 2007). We did not, however, conduct a subgroup analysis according to antibiotic sensitivity in this systematic review as few eligible studies reported antibiotic resistance testing. Increased duration significantly increased the eradication rate for PCA but was not significant for PCN. There is a trend towards the increased duration of PCN being less beneficial than for PCA and PAN. This suggests that the therapeutic window for PCN is wider and that variations in treatment beyond 7 days do not confer much additional benefit. However, this does not give any indication as to which regimen is preferable, as PCA and PCN were not compared directly and it is therefore not possible to determine which regimen had the better eradication rate overall. Only two studies reported the eradication rate of different durations for the PAQ regimen. Although a significant difference was seen between 14 days versus 7 days and 10 days versus 7 days, it is not known whether this finding would be replicated by future studies. Only one study reported data for PANi for 10 days versus 7 days, and the increased eradication rate that was seen with 10 days was not significant. Baseline disease has also been reported to influence H. pylori eradication rates. Some studies suggest that eradication regimens have a greater efficacy in patients with PUD compared to FD patients (Broutet 2003; Schmid 1999) and that this has biological plausibility based on several hypotheses (Gisbert 2001a). If this hypothesis is correct then patients with FD may warrant a prolonged duration of therapy while the small increase in the eradication rate in patients with PUD might not be cost-effective (Gisbert 2001b). In addition, the risk factors identified for eradication failure were suggested to be different between PUD and FD (Broutet 2003). In this systematic review, five PCA studies concluded that no significant difference in the eradication rate was found between patients with PUD and FD (Filipec Kanizaj 2009; Maconi 2001; Paoluzi 2006; Riquelme 2007; Vakil 2004). Only six studies (Calvet 2005a; Ching 1998; De Francesco 2004; Maconi 2001; Riquelme 2007; Vakil 2004) provided eradication data separately for different durations for PUD as well as FD subgroups. In one study, “When patients were grouped into PUD and FD, the overall eradication rate was significantly higher in PUD than in FD; and this difference was statistically significant in both 7-day and 10day triple therapies”; although the overall eradication rate with 10 days was not significantly higher than with 7 days (De Francesco 2004). However, most studies that mixed patients with PUD and FD did not provide data for PUD and FD separately. In the cur-


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rent systematic review, PPI regimens PCA 14 days versus 7 days, PCA 10 days versus 7 days, PCN 14 days versus 7 days, and PAN 14 days versus 7 days have subgroup data for PUD and non-PUD diseases at baseline. For PCA 14 days versus 7 days, RR for H. pylori persistent was significant in PUD (NNT 15) but not in FD patients (Analysis 4.3). ; and no significant subgroup difference was seen. For PCA 10 versus 7 days, significant treatment effect between durations was shown for the subgroup of non-PUD (NNT 14) but not for the subgroup of PUD, and there was significant heterogeneity between the two subgroups. No significant heterogeneity between studies was seen and no significant subgroup difference was seen (Analysis 5.3). The result is similar to Fuccio’s meta-analysis, “a slight but statistically significant increase in eradication rate after a 10 days course compared with 7 days therapy in patients with FD but not in those with PUD“ (Fuccio 2008). This may be due to the inconsistent results shown between PCA 14 versus 7 days compared to PCA 10 versus 7 days, and the fact that some studies mixed patients with PUD and non-PUD diseases without providing eradication rates for the subgroups. Also, some subgroups have a limited number of studies and we cannot draw a definite conclusion that patients with FD are more likely to benefit from prolonging the duration based on our meta-analysis. For the other two regimens that have fewer studies, for PCN 14 days versus 7 days, no significant effect differences between the durations were shown for the PUD and FD subgroups, as well as the total studies (Analysis 7.3). For PAN 14 days versus 7 days, a significant treatment effect between durations was seen only for the PUD subgroup (NNT 10) and the total studies but not for the FD subgroup (Analysis 9.3). Again, no subgroup difference was seen for both comparisons. As a result, although the pooled eradication rate might be increased with PUD patients compared to FD patients, the effect difference of prolonged durations between PUD and FD patients is unclear. Some studies also investigated risk factors for H. pylori eradication failure, while treatment duration was usually one of the predictors in the analyses. Due to limited information, it is not clear whether some risk factors for H. pylori eradication failure (for example, age, smoker, previous treatment, antibiotics resistance) have an impact on the estimated effect size between durations (Broutet 2003). PPI + bismuth + two antibiotics quadruple therapy Bismuth-based PPI, tetracycline, and metronidazole quadruple therapy is an alternative first line therapy in guidelines (Malfertheiner 2012a). In the current meta-analysis, only six studies (n = 1157) provided data for PPI + bismuth + two antibiotics quadruple therapy. H. pylori eradication was compared for 14 days versus 7 days, 10 days versus 7 days, and 14 versus 10 days. None of the comparisons suggest that increased duration significantly improved treatment effect for bismuth-based PPI quadruple therapy. An early meta-analysis of five studies concluded that PPI-based triple therapy, quadruple therapy was comparable in regard to H. pylori eradication (OR 1.00, 95% CI 0.64 to 1.57) (Gene 2003a,

Gene 2003b); which was the case in regions such as Europe (Buzás 2006) and Canada (Rodgers 2007). With the decreasing eradication rate with triple therapy, classic quadruple therapy (consisting of a PPI, bismuth, metronidazole and tetracycline, PBMT) provides high average eradication rates even in areas where metronidazole or clarithromycin resistance is present if given for 10 to 14 days, with similar adherence and adverse events compared to triple therapies (Fischbach 2004). PBMT quadruple therapy for 7 to 10 days therapy is very effective in areas where metronidazole resistance is low and clarithromycin resistance is high, but many areas of the world have prevalent metronidazole resistance nowadays (Vakil 2009). Resistance to either clarithromycin or metronidazole, but not both simultaneously, may be overcome by using quadruple therapies, especially for quadruple therapies containing both clarithromycin and metronidazole, which is most efficacious (Fischbach 2007). In a later meta-analysis of eight RCTs, quadruple and triple therapies are equally effective in eradicating H. pylori infection, but only in the overall analysis and studies since 2003 (Luther 2008). The most recent meta-analysis (9 RCTs, N = 1679) from the same authors concluded that both bismuth-based PPI quadruple therapy and PCA yielded similar eradication rates, but both are suboptimal (78.3% versus 77.0%) with similar compliance and side effect rates (Luther 2010). Although quadruple regimens are not better than triple therapies, they may be the choice for patients allergic to penicillin or for a non-penicillin allergic patient who has received a macrolide antibiotic within five years. Current strategies in most Western countries initiate therapy with a PCA while reserving quadruple PBMT therapy for rescue therapy (Vakil 2009). The ACG guideline and Maastricht consensus recommend quadruple therapy as the alternative first line therapy (Chey 2007; Malfertheiner 2012a), and it is suggested that PPI quadruple therapy should be the first line approach in some regions (Fischbach 2004; Vilaichone 2006). PPI quadruple therapy is usually prescribed for 10 to 14 days. In our meta-analysis only six PPI bismuth quadruple studies investigated the duration effect with different antibiotics but no significant difference was seen between 14, 10 days, and 7 days. Of them, combined antibiotics included tetracycline and metronidazole, furazolidone and amoxicillin, and clarithromycin and amoxicillin. It is unclear whether this marginal improvement in eradication rate by prolonging the duration outweighs the disadvantage of the more complex quadruple therapy. Therefore, we can not draw solid conclusions on the duration effect for PPI quadruple therapy, especially for the duration of 10 days or longer, although quadruple therapy may also be used in a clinic as first line therapy. Adherence is a concern for quadruple therapy due to the complexity of the regimen (Buring 1999; Cockburn 1987); although compliance and adverse events have been shown to be similar to triple therapies (Luther 2010). A meta-analysis of adverse events with bismuth salts (35 RCTs) suggests that bismuth for the treatment of H pylori is safe and well tolerated; the most commonly occurring adverse event was dark stools (Ford 2008). In the current


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meta-analysis, increased duration from 14 days to 7 days is associated with an increase in the proportion of patients who discontinued treatment due to an adverse event, however only two studies were included. No significant difference was seen for the proportion of patients with adverse events nor the proportion of patients with individual adverse events, except the proportion of patients who reported unfitness or discomfort and who reported fatigue or weakness was significantly increased with 14 days treatment compared with 10 days. The development of recent formulations have lessened the pill burden (Baker 2008) and makes quadruple therapy easier for patients (for example, bismuth biskalcitrate, metronidazole, and tetracycline when combined in a new three-inone single capsule) (Spénard 2005) and provides similar efficacy (Laine 2003). Current opinion suggests bismuth-based quadruple therapy is the best option in areas with high clarithromycin resistance (Malfertheiner 2012b). More regions may use PPI bismuth quadruple therapy as first line therapy to overcome bacterial resistance and we may see a benefit of extended duration if more studies are published.

PPI + three antibiotics quadruple therapy Only one study provided data for PPI + three antibiotics quadruple therapy and the duration investigated was 10 days versus 7 days (Basu 2011). Antibiotics used were levofloxacin 250 mg od, nitazoxanide 500 mg tid, and doxycycline 100 mg od. H. pylori eradication was not significantly different between 10 days and 7 days (Analysis 17.1). Adverse events were only reported as patients who discontinued treatment due to adverse events, and no significant difference was seen (Analysis 17.2). As the only RCT compared two durations for PPI + three antibiotics quadruple therapy, both durations reached a promising eradication rate (near 90%) with an absolute increased eradication rate of 17% compared with a standard triple therapy LAC, although the benefit of prolonged duration is not shown. This is a novel but expensive regimen and further evaluation in rigorous clinical studies is warranted (Watson 2011).

PPI + one antibiotic dual therapy In this systematic review, only two studies provided data for PPI dual therapy;,and compared H. pylori eradication for 14 days versus 7 days and 10 days versus 7 days, respectively. No significant difference was shown for the H. pylori eradication rate between 14 days and 7 days, nor was a difference seen between 10 days and 7 days. The antibiotic used was clarithromycin 500 mg bid and levofloxacin 500 mg od, respectively. The proportion of patients with adverse events was significantly increased with a high dose for 14 days versus 7 days (NNTH 4).

H2 RA + bismuth-based quadruple therapy

In theory, PPI-based quadruple or triple therapies should be more effective overall than H2 RA-based quadruple or triple therapy, because of a synergic pharmacokinetic interaction of PPIs with antibiotics and the fact that PPIs are superior to H2 RAs in gastric acid suppression (Gisbert 2005c). In this systematic review, only three studies reported data for H2 RA bismuth quadruple therapy. One used H2 RA + bismuth + two antibiotics for 14 versus 7 days, and two used RBC + two antibiotics for 10 versus 7 days. The only 14 days versus 7 days study suggested a significantly increased eradication rate with 14 days but the eradication rate was very low (NNT 3). H. pylori eradication was not significantly different between 10 days and 7 days. No significant difference was seen for patients with adverse events or individual adverse events. The two included 10 versus 7 days studies used RBC plus two antibiotics. We put this so called ’RBC-based triple therapy’ by other authors into the H2 RA-bismuth quadruple therapy group because RBC is a compound that combines ranitidine and bismuth salt with the purpose of providing both the antisecretory activity of ranitidine and the antipepsin and anti-H. pylori effects of bismuth (Gisbert 1999). The solubility of RBC at lower pH values is two-fold higher than the equimolar admixture of bismuth citrate and ranitidine (McColm 1996). Therefore, combining the pills of H2 RAs and bismuth is used less than RBC. Traditional triple therapies used to be referred to as PPI or RBC plus two antibiotics (any two of amoxycillin, clarithromycin, or metronidazole) and represent the first line regimens administered for 7 to 14 days as recommended by previous European and American guidelines (Howden 1998; Malfertheriner 2002). Previous meta-analyses show comparable pooled eradication rates with one-week RBC-based triple therapy and PPI-based triple regimens (Buzás 2006; Gisbert 2005b); RBC-based triple therapy has a significantly higher eradication rate than PPI triple therapy when prescribed with clarithromycin and a nitroimidazole, perhaps due to the synergistic interaction of RBC with metronidazole even against resistant strains (Gisbert 2005b). Like other first line regimens, the RBC-based eradication therapy has low effectiveness in some regions in recent years (Uygun 2007); although RBC-based triple therapy with metronidazole and amoxicillin (or tetracycline) for 10 to 14 days may still be used as rescue therapy (Di Mario 2006). Due to the limited number of studies, which were reported more than 10 years ago, H2 RA bismuth regimens are usually prescribed for 10 to 14 days and no conclusion could be drawn in terms of the impact of treatment duration on efficacy for this regimen. H2 RA bismuth triple therapy In the current systematic review, two studies compared 14 days with 7 days for RBC 400 mg bid plus clarithromycin 500 mg bid. The H. pylori eradication rate was not significantly different between 14 days and 10 days. Patients with adverse events and reported individual adverse events were not significantly different between the durations. This regimen was also named as ’RBCbased dual therapy’ because RBC was combined with an antibiotic.


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The H. pylori eradication rate for RBC-based dual therapies lasting 7 to 14 days was comparable with RBC-based triple therapies in an earlier meta-analysis (Buzás 2006). The eradication rate was low for both durations, although the studies were published more than eight years ago. Due to the limited number of studies, no definite conclusion could be drawn on the impact of treatment duration on efficacy for this regimen. H2 RA + two antibiotics triple therapy In the current review, three studies reported data for H2 RA triple therapy regimens of 14 versus 7 days with no significantly increased eradication rate with 14 days, and no significant difference was seen for patients with adverse events or reported individual adverse events. Previous meta-analyses suggested that PPIs are more effective than H2 RAs when prescribed at usual doses combined with two antibiotics (Buzás 2006; Gisbert 2003). H2 RA triple therapy is seldom used in practice these days. All eligible studies in this review were from Asia; the latest study in 2008 used lafutidine, which is a second generation H2 RA but it is only marketed in Asia. It is still debatable whether the PPI can be replaced by new generation H2 RAs; although limited Asian RCTs suggest lafutidinebased triple therapy is as effective and as safe as PPI-based triple therapy for first line (Ren 2010) or second line therapy (Kudo 2012). The only study of lafutidine in this review does not suggest that prolonged duration of H2 RA therapy significantly increases treatment efficacy.

Bismuth salt + two antibiotics triple therapy Two studies compared 14 day treatment with 7 day treatment for bismuth salt + two antibiotics triple therapy. One study used BSS while another used CBS. H. pylori eradication was not significantly different between 14 days and 7 days. Patients with adverse events and individual-reported adverse events were not significantly different between the durations. Both studies were published approximately 20 years ago. Traditional bismuth-based triple therapy consists of a bismuth salt and two antibiotics. In 1994, the NIH consensus recommended the bismuth-based triple therapy as one of theH. pylori eradication regimens (NIH 1994). Early pharmacoeconomic analysis suggested the combination of bismuth, metronidazole, and tetracycline (BMT) triple therapy for 14 days as a low cost and low recurrence regimen that was similar to PCN for 7 days and PBMT for 7 days (Taylor 1997). Later studies then showed that bismuth triple therapy for 14 days was significantly inferior to PPI bismuth quadruple therapy and less well tolerated than both 7 days PPI quadruple and PPI triple therapies (Katelaris 2002). Bismuth triple therapies are less commonly used.

Overall completeness and applicability of evidence

This systemic review included randomised controlled trials without restriction due to publication status or language of publication. We searched several databases and conference proceedings, and contacted experts in the field for any possible trials for inclusion in the review. We included trials of any H. pylori eradication regimen that compared the most common durations of 7, 10, or 14 days. We recognize that it is impossible to identify all grey literature, and no language restriction in certain databases does not equate to covering all language databases (Pilkington 2005). Although we searched for RCTs in any language, limited databases prevent us from retrieving all published literature. For example, although we identified several Korean abstracts online, we were not able to retrieve the full reports of the studies. We only included one Korean study, but two meta-analyses from Korea reported that they included 10 Korean journal articles comparing the eradication rate with different durations and concluded that prolonged duration of first line triple therapy significantly increased the H. pylori eradication rate in Korea for all three duration comparisons (Jung 2008). We tried to contact the authors but were not able to retrieve the original articles to see whether all 10 articles met our inclusion criteria. Eligible studies came from North or South America, Europe, Asia, or South Africa. The participants included in the reviewed covered most indications for H. pylori eradication including PUD, FD, chronic mucosal inflammation, etc, although bleeding patients and cancer patients were not included due to the nature of the trials. The broad spectrum of patients selected, as well as the wide variety of tests used for H. pylori diagnosis or eradication assessment, reflect the results in real world practice. Hence, we believe this review is comprehensive and that the results reflect the available evidence for the treatment effect of durations on first line H. pylori eradication. The major results and those from the subgroup and sensitivity analyses are consistent, suggesting that the conclusion that ’increasing the PPI triple therapy duration from 7 days to 14 days significantly increases H. pylori eradication rate’ is generalisable and the evidence is applicable in most of the countries. It is appreciated that we do not recommend the type of regimen which should be used for first line therapy in the current era of increasing antibiotic resistance, and we don’t believe a ’best regimen’ should be recommended for all countries; but we agree treatment strategies that work locally should be the choice and a treatment duration of 14 days should be considered, especially when an eradication rate of 7 days or 10 days is suboptimal.

Quality of the evidence In the current systematic review, only two of 75 studies were assessed to have a low risk of bias for all eight risk domains (Kim 2008; Zagari 2007); and 43 were assessed to have a high risk of bias due to at least one risk domain being assessed as high risk. Concealment of allocation was judged as adequate in only 11 eligible studies and inadequate in three studies. The remaining 61 stud-


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ies were considered to have an unclear risk for allocation concealment bias because no detailed information was provided regarding the allocation concealment. We performed a subgroup analyses (planned a priori) based on the overall risk of bias and allocation concealment. In comparisons where eradication was significantly increased with increased duration, the effect size remained significant for the subgroup of overall unclear risk studies as well as for studies with unclear risk of allocation concealment; with a similar effect size to that of all studies. Although the effect size in high risk or low risk of bias subgroups remained significant or became insignificant, the number of studies is fewer in these subgroups, therefore the results of these subgroup analyses are considered to be less reliable. For duration comparisons where no significant effect was seen, no significant treatment effect was seen when the studies were further broken down by risk subgroups. Therefore we cannot draw a definitive conclusion on whether the treatment effect is impacted by the allocation concealment or the overall risk of bias of the studies. Overall, the quality of evidence for the outcome of H.pylori persistence for PPI triple therapy is moderate because of study limitation (risk of bias). For certain subgroups, quality of the evidence for the outcome H.pylori persistence is low (e.g., PCN 14 days versus 7 day) or very low (e.g., PCN 10 days versus 7 days) because of study limitation and imprecision. Imprecision is considered when only a few studies were eligible (1 to 5 studies) with small total number of events (< 300). The quality of evidence for the outcome of adverse events is moderate (14 days versus 7 days and 10 days versus 7 days) to low (14 days versus 10 days) because of study limitation and imprecision (Summary of findings for the main comparison; Summary of findings 2; Summary of findings 3). Considering the consistencies of the results of PPI triple therapy, with improved quality of the evidence, future studies with improved reporting and methodological quality are unlikely to change the conclusion. However, further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Potential biases in the review process We explored publication bias (or other small study effects) using funnel plots and tested for funnel plot asymmetry by the Begg, Egger and Harbord tests where there were at least 10 studies included in the meta-analysis. For dichotomous outcomes measured as relative risk, potential problems in funnel plots have been less extensively studied and firm guidance is not yet available. Therefore, we reported results for assessing funnel plot asymmetry using three methods. The results indicated that publication bias or other small study effects may be present for the outcome of H. pylori persistence in the comparison of all PPI triple therapy 14 versus 7 days (Figure 3). It is possible that studies with insignificant results were not published, or potentially poor methodological quality led to inflated effects in smaller studies. In addition, the value of the

tests for asymmetry reduce when there is significant heterogeneity between studies. The tests for funnel plot asymmetry showed reduced significance as well as discordant results (PCA 14 days versus 7 days) or become non-significant (PAN 14 days versus 7 days) when the analyses were performed by regimens. The Egger test (Egger 1997) is the most commonly used method that tests for asymmetry of the funnel plot, but the power of this method to detect bias is low with small numbers of studies, or it can result in a false positive when there are large treatment effects and few events per trial. The Begg test (Begg 1994) bias indicator makes fewer assumptions than the Egger test but it is insensitive to many types of bias so the Begg test has very low power to detect biases unless there are many studies (Sterne 2000). The Harbord test (Harbord 2006) maintains the power of the Egger test while reducing the false positive rate especially when there are large treatment effects, few events per trial, or all trials are of similar size. However, the Egger test should be used instead of the Harbord method if there is a large imbalance between the sizes of treatment and control groups. In this review, data from the three methods are consistent except for the group of PCA 14 days versus 7 days, where the P value for Egger’s test = 0.02 but the P values for the Begg test and Horbold test were 0.06 and 0.06, respectively. There are 34 studies in this group so the discrepancy is not due to a lack of power. A visual inspection of the funnel plot suggested near symmetry but there were several imbalanced studies between the size of the treatment and control groups. The slope of coefficient is low (not much greater than 1), therefore the clinical importance of this publication bias or small study effect is likely to be small. Currently, potential problems in funnel plots have been less extensively studied for risk ratio as the effect measures than for odds ratios, and firm guidance is not yet available (Chapter 10, Cochrane 2011). None of these tests for funnel plot asymmetry have been validated against a gold standard, and the explanation for the detected bias varies. Based on a survey of meta-analyses published in the Cochrane Database of Systematic Reviews, tests for funnel plot asymmetry should be used in only a minority of meta-analyses (Ioannidis 2007). Our example also demonstrates that we need more studies as well as guidance on how to interpret the tests of reporting bias, especially for risk ratio. Another potential limitation was the moderate but significant heterogeneity which was noted for the overall PPI triple therapy 14 days versus 7 days. The heterogeneity was explored by the type of regimen, and can be explained by the differences in regimens, geographic locations, baseline disease, and risk of bias. As discussed, some other factors that potentially introduce clinical bias were not able to be assessed in this review due to limited information, such as pre-treatment antibiotic resistance, H. pylori strains, preor post-eradication antisecretory drugs, and the variable tests for assessing H. pylori infection or variation. Furthermore, the inclusion of predominantly high or unclear risk of bias trials in the subgroup analyses may have biased our effect estimates. Although the


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subgroup and sensitivity analyses point to the same treatment effect direction, we should consider the clinical heterogeneity when the results are applied. For some of the duration comparisons or regimens, less than three studies were available with a small number of patients; therefore, the results are uncertain for these comparisons. Although we preplanned several subgroup analyses under each comparison (for example, regimens, geographic location, baseline disease, and risk of bias) we should bear in mind that multiple subgroup analyses have a high chance of finding some ’significant results’ due to the play of chance and therefore the results should be interpreted with caution (Counsell 1994). To properly answer some of the clinically important questions, we should consider using the method of individual patient data meta-analysis, which is considered to be a ‘gold standard’ of systematic review and which could be used to more fully investigate the influence of covariates on heterogeneity of treatment effects, both within and between trials (Clarke 2005; Simmonds 2005), instead of the meta-analysis at the study level. Except for the H. pylori eradication and adverse events, we do not know whether other outcomes (for example, mucosal inflammation and ulcer healing) are also significantly different between different treatment durations. Prospective clinical trials are necessary to answer these questions. Furthermore, although we studied durations within two weeks, we only chose the most common durations (7, 10, 14 days) for comparisons, although other durations within 14 days have been studied (for example, 1, 3, 4, 6, 12 days) (Treiber 2000). Even 12 days may have more efficacy than 10 days or 7 days, although these ’irregular’ durations are unlikely to be widely accepted in practice. Finally, we appreciate that systematic reviews rigorously evaluate and summarize current knowledge, and meta-analyses provide a more reliable and enhanced precision of effect estimate than do individual studies and can answer some uncertainties. However, there are also some limitations since systematic reviews are observational research projects and therefore subject to bias, and the quality depends on the extent which scientific review methods are used. For example, errors are common in the conduct of systematic reviews (Ford 2010b) and overstating the evidence, such as double counting and assigning spurious precision to individual studies in meta-analysis, is also common and problematic (Senn 2009). Although we have tried to use rigorous research methods when performing this meta-analysis, especially to avoid inappropriate data handling and over counting, we cannot avoid all possible biases particularly if the data were originally misreported. We should be aware of this possible limitation when interpreting the results. According to Cochrane Collaboration policy we performed an additional literature search in October 2013, prior to the publication of the review. We identified eight studies which may be eligible for inclusion in this review (Chen 2013; Choi 2012; Fallone 2013; Konorev 2012; Lv 2013; Prasertpetmanee 2013; Wang 2013; Xu 2012). These studies have not yet been assessed or included in our review. They will be systematically assessed and, if eligible they

will be included in the next version of this review. While it is uncertain how the new studies would impact on our confidence in the results, it is unlikely that there will be a substantial change in our conclusions.

Agreements and disagreements with other studies or reviews There are substantial differences between the current systematic review and the six previous systematic reviews (three published reviews and three presented as conference proceedings) (Calvet 2000; Ford 2003; Fuccio 2007; Kim 2001b; Jung 2008; Flores 2010). The detailed differences are documented in Table 2. First, this systematic review searched more databases, more conference proceedings, and identified more eligible studies than all previous meta-analyses. We considered the same cut-off time point and same inclusion criteria as published systematic reviews (Yuan 2009). This review has no language restriction while a previous review only included English only studies (Fuccio 2007) and two reviews published in abstract format only included Korean trials (Jung 2008; Kim 2001b). This review included any H. pylori eradication regimen, including any PPI triple regimen, while previous reviews either only included OAC studies (Kim 2001b; Jung 2008), or PAC or PCN studies (Calvet 2000; Fuccio 2007), or only PPI triple regimens (Flores 2010; Ford 2003). This review included eligible trials that compared 7, 10, or 14 days, while some published reviews did not compare 10 and 14 days (Ford 2003). Therefore, this review is more comprehensive compared to published reviews and the results reflect the real world practice better. This review comprehensively listed all eligible tests for H. pylori diagnosis as well as tests for assessing eradication, which reflect the current knowledge we have for diagnostic tests. While most of the previous reviews considered H. pylori eradication as the only outcome (Ford 2003; Fuccio 2007; Kim 2001b; Jung 2008), this review studied the adverse events by reporting the effect of treatment duration on patients with adverse events, patients who discontinued treatment due to adverse events, and individual adverse events. Therefore, we have efficacy as well as a safety profile of the treatment strategies. We tried several strategies to minimize bias when performing this study. Inclusion and exclusion criteria were set up a priori, and data extraction was pre-tested on several studies. Two independent investigators judged the study eligibility and two review authors extracted the data and assessed study quality independently. We identified several errors in previous meta-analyses. For example, two studies were erroneously excluded by Fuccio et al (Fuccio 2007), interpreted as being not first line eradication therapy (Gumurdulu 2004; Paoluzi 1998). Fuccio’s meta-analysis claimed to include only standard dose regimens and excluded one study for not being of the recommended doses (Bhasin 2000), but they included and mixed four studies which used low doses of clarithromycin or PPI (Dal Bo’N 1998; Hurenkamp 2000; Louw 1998; Scaccianoce


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2006). Moreover, one French historical control study (Lamouliatte 1998; Lamouliatte 2000) was mistakenly included in Calvet and Ford’s meta-analyses as an RCT (Calvet 2000; Ford 2003). This review only included studies that reported ITT results and used a more strict definition for ITT, while a previous review included studies that only provided data in the PP sample (Calvet 2000). We performed subgroup analyses that were planned a priori to examine sources of heterogeneity and identify patient groups that may respond differently to prolongation of therapy. We calculated RR by random-effects models and performed fixed-effect models and calculated OR in the sensitivity analyses. Our results are robust after sensitivity analyses. All previous reviews concluded that extending duration from 7 days to 14 days significantly increased eradication rate, except a previous meta-analysis concluded ”that extending triple therapy beyond 7 days is unlikely to be a clinically useful strategy“, because it overemphasized the difference in the absolute eradication rate (4% to 5%) between the durations of treatment and compared this rate with that from other meta-analyses (Calvet 2000; Ford 2003) but ignored the significantly increased H. pylori eradication rate which favoured longer duration for PCA and the overall analysis (Fuccio 2007; Fuccio 2009; Yuan 2009). Instead of simply separating the studies as amoxicillin-based and metronidazole-based triple therapy (Fuccio 2007), we calculated effect size for PCA, PCN, PAN, and other PPI triple therapy regimens individually, which provides a more detailed overview of the evidence. This meta-analysis evaluated the presence of statistical heterogeneity but also investigated the presence of clinical heterogeneity. The presence of publication bias or other small study effects was examined by both graphical and statistical evaluations. Compared to other meta-analyses, we calculated the NNT and NNTH in addition to the RR, which gave another quantitative scale for the reader to interpret and apply the treatment effect (Cook 1995), although the interpretation of NNT and NNTH should be used with caution (Hutton 2010).

AUTHORS’ CONCLUSIONS Implications for practice This review suggests that increasing the duration of PPI-based triple therapy increases H. pylori eradication rates. For PCA, prolonging treatment duration from 7 to 10 days or from 10 to 14 days is associated with a significantly higher eradication rate. The optimal duration of therapy for PCA and PAN is at least 14 days. More data are needed to confirm any benefit of increasing duration of therapy for PCN therapies. Only limited data were reported on different durations for regimens other than PPI-based triple therapy, such as the alternative first line regimen bismuth-based quadruple therapy. More studies are needed to draw meaningful conclusions for optimal duration of H. pylori eradication regimens other than for PPI-based triple therapy. As part of the ongoing

Cochrane review, this study used the most rigorous methodology to perform a systematic review and meta-analysis of this topic. The final results give updated evidence to support recommendations for the optimum duration of an H. pylori eradication regimen for future international guidelines, and subsequently will have an impact on daily practice worldwide.

Implications for research To minimize clinical heterogeneity, this review suggests further studies should reduce the risk of bias in both design and performance stages; reporting quality should be improved according to the CONSORT statement (Begg 1996; Tuner 2012), especially for the methods section; reporting of adverse events should be standardized and completed; standard methods for H. pylori diagnostic and eradication assessment should be used; results for important subgroups, such as baseline diseases, should be reported. Future trials can consider investigating some other clinical important questions, such as the treatment effect of duration on different PPIs and antibiotics or different doses, pre-treatment antibiotic resistance versus susceptible stains, with or without pre- or posteradication PPIs, race and CYPC19 genotype, etc. We would like to point out that that we did not perform a cost-effectiveness analysis for the optimum duration of H. pylori eradication regimens but economic considerations are becoming increasingly important (Moayyedi 2002; Moayyedi 2007). Based on their literature search up to 1999, Calvet performed the only cost-effectiveness analysis to study the optimal length of PPI triple therapies for H. pylori. The authors concluded that 7-day therapies seem to be the most cost-effective strategy, but the difference was more evident in Spain where the cost of H. pylori eradication therapy is low, but less evident in USA where costs are higher (Calvet 2001). Cost-effectiveness analysis should take into account both the local costs and eradication rates using economic models to extrapolate data from a variety of sources. The same treatment strategy may be cost-effective in one region but not another. For example, H. pylori eradication for functional dyspepsia is cost-effective in Europe compared to no treatment, but the cost-effectiveness is less certain in the USA due to H. pylori eradication therapy being more expensive (Moayyedi 2007). Since the current meta-analysis has updated the eradication rate with more eligible studies and more countries, an updated analysis of cost-effectiveness based on new data should be performed before we can recommend the optimum duration of H. pylori eradication regimen in a given region. Sequential therapy is a hot topic in recent years, with promising results. The duration also extends to 10 days but different antibiotics are used in the first and second weeks (Gatta 2009; Gatta 2013; Greenberg 2011). We excluded studies that compared treatment duration for sequential therapy from this review (e.g. 10 days vs 14 days sequential therapy, Liou 2013) because the antibiotics used are different for two different sequences within the same regimen. Future studies and systematic reviews should inves-


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tigate the duration effect on sequential therapy. Adding the third antibiotic as the ’four drugs non-bismuth concomitant therapy’ may be another alternative regimen by reducing the complexity of sequential therapy but providing superior eradication rates than triple therapy (Essa 2009; Gisbert 2011). However, we do not have eligible studies for non-bismuth concomitant therapy that compared different durations. Thus, we can not answer the question of whether prolonged durations for these novel regimens will significantly increase H. pylori eradication rates. New evidence may help us to answer this question. With more novel and alternative eradication regimens proposed, they might replace triple therapy even for 14 days to reach an acceptable (> 85%), good (> 90%), or excellent (≥ 95%) eradication rate (Graham 2008). Hybrid therapy consists of 14 days therapy with a PPI and an antibiotic (e.g. omeprazole and omeprazole), adding another two antibiotics for the final 7 days (e.g. clarithromycin and tinidazole/metronidazole). Preliminary evidence suggest hybrid therapy reached a lower eradication rate than sequential and concomitant therapies (Zullo 2013). Therefore, our knowledge should be updated to include new evidence and to think beyond the results of this meta-analysis.

ACKNOWLEDGEMENTS We thank Karin Dearness, Managing Editor, Cochrane Upper Gastrointestinal and Pancreatic Diseases (UGPD) Group, for providing administrative and logistical and editing support for the conduct of the current review. We thank Professor Ann McKib-

bon, Health Information Research Unit, Department of Clinical Epidemiology & Biostatistics, McMaster McMaster for her advice in optimising literature search strategies. We thank Racquel Simpson, Trials Search Co-ordinator of the UGPD, for her help in the literature search for this review. We acknowledge the language translation help in study eligibility assessment and/or data extraction from the following colleagues: Dr Jose Santana (Spanish), Dr Eric-Jean (French), Mrs Joan Nam (Korean), Dr Masako Tanaka (Japanese) and Dr Irene T Padol (Polish). We appreciate the following authors provided us raw data or information for their studies: Dr Maria Pina Dore (University of Sassari, Italy); Dr Mohammad H Emami (Isfahan University of Medical Sciences, Iran); Dr Changwoo Gham (Kwandong University, Korea); Dr Tajana Filipec Kanizaj (University hospital Merkur, Croatia); Dr Bora Keum (Korea University College of Medicine, Korean); Dr Nayoung Kim (the Catholic University of Korea, Korea); Dr Keisuke Kiyota (Kiyota Clinic, Japan), Dr Manabu Nakagawa (Hokkaido University Hospital, Japan); Dr Paolo Paoluzi (University of Rome, Italy); Dr Rinaldo Pellicano (Giovanni Battista (Molinette) Hospital, Torino, Italy); Dr Francisco C Ramirez (Hayden Veterans Affairs Medical Center, Arizona, USA); Dr Vincenzo Savarino (University of Genoa, Italy); Dr Renzo Suriani (Ospedale Nuovo Rivoli, Italy) and Dr Angelo Zullo (Nuovo Regina Margherita hospital, Roma, Italy). We are thankful to Dr Noori Akhtar-Danesh and Dr Forough Farrokhyar, who have offered invaluable advice to the methodology.

REFERENCES

References to studies included in this review Antelo 2001 {published data only} Antelo P, Almuzara M, Avagnina A, Topor J, Barberis C, Barcia T, et al. Diagnosis and treatment of Helicobacter pylori infection. Relationship with gastrointestinal ulcer and antimicrobial resistance [Diagnostico y tratamiento de la infeccion por Helicobacter Pylori su relacion con la ulcera gastrointestinal y la resistencia a los antimicrobianos]. Medicina (B Aires) 2001;61(5 part 1):545–51. Aydin 2007 {published data only} Aydin A, Onder G, Akarca U, Tekin F, Tuncyurek M, Ilter T. Comparison of 1- and 2-week pantoprazole-based triple therapies in clarithromycin-sensitive and resistant cases. European Journal of Internal Medicine 2007;18(6):496–500. Bago 2010 {published data only} Bago J, Majstorovi

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randomized controlled trial. Annals of Clinical Microbiology and Antimicrobials 2010;9(13):1–6. Basu 2011 {published data only} Basu PP, Rayapudi K, Pacana T, Shah NJ, Krishnaswamy N, Flynn M. A randomized study comparing levofloxacin, omeprazole, nitazoxanide, and doxycycline versus triple therapy for the eradication of Helicobacter pylori. American Journal of Gastroenterology 2011;106(11):1970–5. Berrutti 2008 {published data only} Berrutti M, Pellicano R, Astegiano M, Smedile A, Saracco G, Morgando A, et al. Helicobacter pylori eradication: metronidazole or tinidazole? Data from Turin, Italy. Minerva Gastroenterologica e Dietologica 2008;54(4):355–8. Bhasin 2000 {published data only} Bhasin DK, Sharma BC, Ray P, Pathak CM, Singh K. Comparison of seven and fourteen days of lansoprazole, clarithromycin, and amoxicillin therapy for eradication ofHelicobacter pylori: a report from India. Helicobacter 2000;5(2):84–7.


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Bosques-Padilla 2004 {published data only} Bosques-Padilla FJ, Garza-González E, Calderón-Lozano IE, Reed-SanRoman G, de Ariño Suárez M, ValdovinosDíaz MA, et al. Open, randomized multicenter comparative trial of rabeprazole, ofloxacin and amoxicillin therapy for Helicobacter pylori eradication: 7 vs. 14 day treatment. Helicobacter 2004;9(5):417–21.

Dammann 2000 {published data only} Dammann HG, Folsch UR, Hahn EG, von Kleist DH, Klör HU, Kirchner T, et al. Eradication of H. pylori with pantoprazole, clarithromycin, and metronidazole in duodenal ulcer patients: a head-to-head comparison between two regimens of different duration. Helicobacter 2000;5(1):41–51.

Calvet 2005a {published data only} Calvet X, Ducons J, Bujanda L, Bory F, Montserrat A, Gisbert JP, et al. Seven versus ten days of rabeprazole triple therapy for Helicobacter pylori eradication: a multicenter randomized trial. American Journal of Gastroenterology 2005;100(8):1696–701.

de Boer 1994 {published data only} de Boer WA, Driessen WM, Potters VP, Tytgat GN. Randomized study comparing 1 with 2 weeks of quadruple therapy for eradicating Helicobacter pylori. American Journal of Gastroenterology 1994;89(11):1993–7.

Chaudhary 2004 {published data only} Chaudhary A, Ahuja V, Bal CS, Das B, Pandey RM, Sharma MP. Rank order of success favors longer duration of imidazole-based therapy for Helicobacter pylori in duodenal ulcer disease: a randomized pilot study. Helicobacter 2004;9 (2):124–9.

De Francesco 2004 {published data only} De Francesco V, Zullo A, Hassan C, Della Valle N, Pietrini L, Minenna MF, et al. The prolongation of triple therapy for Helicobacter pylori does not allow reaching therapeutic outcome of sequential scheme: a prospective, randomised study. Digestive and Liver Disease 2004;36(5):322–6.

Chew 1994 {published data only} Chew K, Eidus L. Clarithromycin and high dose omeprazole for H. pylori eradication: a comparison on one and two week therapy. Gastroenterology 1994;106 (4, Pt2):A 62.

Di Caro 2002a {published data only} Di Caro S, Zocco MA, Cremonini F, Candelli M, Nista EC, Bartolozzi F, et al. Levofloxacin based regimens for the eradication of Helicobacter pylori. European Journal of Gastroenterology and Hepatology 2002;14(12):1309–12.

Ching 1998 {published data only} Ching CK, Chan YK, Ng WC. The combination of omeprazole, amoxycillin, and clarithromycin eradicates Helicobacter pylori in 95% of patients --7 days of therapy is as good as 10 days. Hong Kong Medical Journal 1998;4(1): 7–10.

Di Mario 2003a {published data only} Di Mario F, Aragona G, Dal Bo N, Cavestro GM, Cavallaro L, Iori V, et al. Use of bovine lactoferrin for Helicobacter pylori eradication. Digestive and Liver Disease 2003;35(10): 706–10.

Cho 2001 {published data only} Cho YJ, Chun HJ, Kim ST, Koh DW, Park JH, Park DK, et al. Analysis of eradication rate of Helicobacter pylori according to treatment duration by using 13C-Urea breath test comparison of OAC 7, 10 or 14 days regimen. [Korean]. Korean Journal of Gastrointestinal Endoscopy 2001; 23(4):207–12. Cui 2002 {published data only} Cui M. Hu F. Jiang H. Comparison of pantoprazole and omeprazole-based triple therapy regimens in the treatment of Helicobacter pylori infection. [Chinese] [ Zheng X Zhonghua Yi Xue Za Zhi (Natlonal Medical Journal of China) 2002;82(18):1245–8. Daghaghzadeh 2007 {published data only} Daghaghzadeh H, Emami MH, Karimi S, Raeisi M. Oneweek versus two-week furazolidone-based quadruple therapy as the first-line treatment for Helicobacter pylori infection in Iran. Journal of Gastroenterology and Hepatology 2007;22(9): 1399–403. Dal Bo’ 1998 {published data only} Dal Bo’ N, Di Mario F, Battaglia G, Buda A, Leandro G, Vianello F, et al. Low dose of clarithromycin in triple therapy for the eradication of Helicobacter pylori: one or two weeks?. Journal of Gastroenterology and Hepatology 1998;13 (3):288–93.

Dore 2011 {published data only} Dore MP, Farina V, Cuccu M, Mameli L, Massarelli G, Graham DY. Twice-a-day bismuth-containing quadruple therapy for Helicobacter pylori eradication: a randomized trial of 10 and 14 days. Helicobacter 2011;16(4):295–300. Emami 2006 {published data only} Emami MH, Saberfiroozi MM, Arj A, Taghavi AR, BagheriLankarani K, Dehbashi N, et al. Does delayed gastric emptying shorten the H pylori eradication period? A double blind clinical trial. World Journal of Gastroenterology 2006; 12(39):6310–5. Ercin 2010 {published data only} ]. Erçin CN, Uygun A, Toros AB, Kantarcio lu M, Kilciler G, Polat Z, Ba ci S. Comparison of 7- and 14-day firstline therapies including levofloxacin in patients with Helicobacter pylori positive non-ulcer dyspepsia. Turkish Journal of Gastroenterology 2010;21(1):12–6. Fennerty 1998 {published data only} Fennerty MB, Kovacs TO, Krause R, Haber M, Weissfeld A, Siepman N, et al. A comparison of 10 and 14 days of lansoprazole triple therapy for eradication ofHelicobacter pylori. Archives of Internal Medicine 1998;158(15):1651–6. Filipec Kanizaj 2009 {published data only} Filipec Kanizaj T, Katicic M, Skurla B, Ticak M, Plecko V, Kalenic S. Helicobacter pylori eradication therapy success regarding different treatment period based on


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clarithromycin or metronidazole triple-therapy regimens. Helicobacter 2009;14(1):29–35.

Hurenkamp 2000 {published data only} Hurenkamp GJ, Van Der Ende A, Grundmeijer HG, Tytgat GN, Van Der Hulst RW. Equally high efficacy of 4, 7 and 10-day triple therapies to eradicate Helicobacter pylori infection in patients with ulcer disease. Alimentary Pharmacology and Therapeutics 2000;14(8):1065–70.

Garza González 2007 {published data only} Garza González E, Giasi González E, Martínez Vázquez MA, Pérez Pérez GI, González GM, Maldonado Garza HJ, Bosques Padilla FJ. Helicobacter pylori eradication and its relation to antibiotic resistance and CYP2C19 status. Revista Espanola de Enfermedades Digestivas 2007;99(2): 71–5.

Kang 2000a {published data only} Kang CD, Chun HJ, Park DK, Hur BW, Lee JW, Jee YT, et al. Significance of pretreatment of delta 13CO2 as predictor of success for H. pylori eradication. Gut 2000;47 Suppl 3: A120. Abstract P365.

Gisbert 2005a {published data only} Gisbert JP, Dominguez-Munoz A, Dominguez-Martin A, Gisbert JL, Marcos S. Esomeprazole-based therapy in Helicobacter pylori eradication: any effect by increasing the dose of esomeprazole or prolonging the treatment?. American Journal of Gastroenterology 2005;100(9):1935–40.

Karatapanis 2011 {published data only} Karatapanis S, Georgopoulos SD, Papastergiou V, Skorda L, Papantoniou N, Lisgos P, et al. 7, 10 and 14-days rabeprazole-based standard triple therapies for H. pylori eradication: are they still effective? A randomized trial. Acta Gastroenterologica Belgica 2011;74(3):407–12.

Grade 1996 {published data only} Grade AJ, Blubaugh FC, Ramirez FC. Clarithromycin, amoxicillin and omeprazole, for eradication of H. pylori: a prospective, randomized, comparative study of a seven day versus ten day course. Gastroenterology 1996;110 Suppl 1: A121.

Katicic 1997 {published data only} Katicic M, Presecki V, Marusic M, Prskalo M, Ticak M, Sabaric B, et al. Eradication of H. pylori infection with two triple-therapy regimens of 7, 10 and 14 days. Gut 1997;41 Suppl 1:A100. Abstract#09/367. Kaviani 2001 {published data only} Kaviani MJ, Malekzadeh R, Vahedi H, Sotoudeh M, Kamalian N, Amini M, et al. Various durations of a standard regimen (amoxycillin, metronidazole, colloidal bismuth sub-citrate for 2 weeks or with additional ranitidine for 1 or 2 weeks) on eradication of Helicobacter pylori in Iranian peptic ulcer patients. A randomized controlled trial. European Journal of Gastroenterology and Hepatology 2001; 13(8):915–9.

Gumurdulu 2004 {published data only} Gumurdulu Y, Serin E, Ozer B, Kayaselcuk F, Ozsahin K, Cosar AM, et al. Low eradication rate of Helicobacter pylori with triple 7-14 days and quadruple therapy in Turkey. World Journal of Gastroenterology 2004;10(5):668–71. Hsu 2005 {published data only} Hsu CC, Chen JJ, Hu TH, Lu SN, Changchien CS. One-week versus two-week H2 -receptor antagonist in combination with amoxicillin and tinidazole for eradication of Helicobacter pylori infection. Hepato-Gastroenterology 2005;52(65):1617–21.

Keum 2005 {published data only} Keum B, Lee SW, Kim SY, Kim MJ, Choung RS, Yim HJ, et al. Comparison of Helicobacter pylori eradication rate according to different PPI-based triple therapy: omeprazole, rabeprazole, Esomeprazole and lansoprazol (in Korean). Korean Journal of Gastroenterology 2005;46(6):433–9.

Hu 1999 {published data only} Hu F, Wang Z, Fan G. Comparison of 1 week and 2 weeks efficacy of lansoprazole triple therapy in treatment of H. pylori infection [ 1 2 Chinese New Drugs Journal 1999;8(4):246–8. Hu 2003 {published data only} Hu FL, Jia JC, Li YL, Yang GB. Comparison of H2 receptor antagonist- and proton-pump inhibitor-based triple regimens for the eradication of Helicobacter pylori in Chinese patients with gastritis or peptic ulcer. The Journal of International Medical Research 2003;31(6):469–74. Hu 2004 {published data only} Hu FL for Multiple Center Study Group In Beijing Area, China. Effects of different triple therapies on duodenal ulcer-associated Helicobacter pylori infection and a one-year follow-up study [ Zhonghua Yi Xue Za Zhi (National Medical Journal of China) 2004;84(14):1161–5.

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Kim 2007 {published data only} Kim BG, Lee DH, Ye BD, Lee KH, Kim BW, Kim SG, et al. Comparison of 7-day and 14-day proton pump inhibitorcontaining triple therapy for Helicobacter pylori eradication: neither treatment duration provides acceptable eradication rate in Korea. Helicobacter 2007;12(1):31–5. Kim 2008 {published data only} Kim N, Park SH, Seo GS, Lee SW, Kim JW, Lee KJ, et al. Lafutidine versus lansoprazole in combination with clarithromycin and amoxicillin for one versus two weeks for Helicobacter pylori eradication in Korea. Helicobacter 2008; 13(6):542–9. Kiyota 1999 {published data only} Kiyota K, Habu Y, Sugano Y, Inokuchi H, Mizuno S, Kimoto K, et al. Comparison of 1-week and 2-week triple therapy with omeprazole, amoxicillin, and clarithromycin ]. patients with Helicobacter pylori infection: in peptic ulcer results of a randomized controlled trial. Journal of Gastroenterology 1999;34 Suppl XI:76–9.


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Knigge 1999 {published data only} Knigge K, Kelly C, Peterson WL, Fennerty MB. Eradication of Helicobacter pylori infection after ranitidine bismuth citrate, metronidazole and tetracycline for 7 or 10 days. Alimentary Pharmacology and Therapeutics 1999;13(3): 323–6. Laine 1996 {published data only} Laine L, Estrada R, Trujillo M, Fukanaga K, Neil G. Randomized comparison of differing periods of twice-aday triple therapy for the eradication of Helicobacter pylori. Alimentary Pharmacology and Therapeutics 1996;10(6): 1029–33. Lee 2004 {published data only} Lee D, Lee S, Chun H, Jung H, Kim J, Korean Helicobacter pylori study group. Two weeks triple regimens with PPI, clarithromycin and amoxicillin is more effective in H. pylori eradication than one week triple regimens in patients with peptic ulcer disease in South Korea. (Multicenter trial by Korean Helicobacter pylori Study Group). Helicobacter 2004; 9 (5):570. Abstract #11.08.

Mesquita 2005 {published data only} Mesquita MA, Lorena SL, Almeida JR, Montes CG, Guerrazzi F, Campos LT, et al. One-week dual therapy with ranitidine bismuth citrate and clarithromycin for the treatment of Helicobacter pylori infection in Brazilian patients with peptic ulcer. World Journal of Gastroenterology 2005;11(23):3566–9.

Louw 1998a {published data only} Louw JA, Van Rensburg CJ, Moola S, Kotze D, Marks IN. Helicobacter pylori eradication and ulcer healing with daily lansoprazole, plus 1 or 2 weeks co-therapy with amoxycillin and clarithromycin. Alimentary Pharmacology and Therapeutics 1998;12(9):881–5.

Muszynki 1992 {published data only} Muszynski J, Czyzyk A, Biernacka D, Pachecka J, Stepka M, Zalewski L. Combined treatment of Helicobacter pylori infection--7-day or 14-day treatment? [Skojarzone leczenie zakazenia Helicobacter pylori–terapia 7 czy 14–dniowa?]. Polski Tygodnik Lekarski 1992;47(29-30):642–5.

Louw 1998b {published data only} Louw JA, van Rensburg CJ, Hanslo D, Grundlings HD, Girdwood AH, Marks IN. Two-week course of pantoprazole combined with 1 week of amoxycillin and clarithromycin is effective in Helicobacter pylori eradication and duodenal ulcer healing. Alimentary Pharmacology and Therapeutics 1998;12(6):545–50.

Nakagawa 1999 {published data only} Nakagawa M, Ooishi M, Yoda Y, Kawamura N, Ooizumi H, Saitou M, Nakagawa S. A comparative study; one week treatment versus two weeks treatment with lansoprazole, amoxycillin and clarithromycin for the eradication of Helicobacter pylori in patient with gastric and duodenal ulcer [Japanese]. Nippon Rinsho 1999;57(1):144–7.

Lv 2011 {published data only} Lv NH, Xie Y, Guo XB, Fan HZ, Tang JH, Zeng XP, et al. Eradication therapy for Helicobacter pylori infection in patients with duodenal ulcers based on furazolidone triple and quadruple therapy: A multicenter randomized controlled trial. Helicobacter 2011;16 Suppl 1:87 Abstract #WS5.3. Maconi 2001 {published data only} ∗ Maconi G, Parente F, Russo A, Vago L, Imbesi V, Bianchi Porro G. Do some patients with Helicobacter pylori infection benefit from an extension to 2 weeks of a proton pump inhibitor-based triple eradication therapy?. American Journal of Gastroenterology 2001;96(2):359–66. Maconi G, Russo A, Imbesi V, Cucino C, Bianchi Porro G. Prolonging proton pump inhibitor-based anti-Helicobacter pylori treatment from one to two weeks in duodenal ulcer: is it worthwhile?. Digestive and Liver Disease 2000;32(4): 275–80. Mantzaris 1999 {published data only} Mantzaris GJ, Tzathas H, Petrak K, Spiliades C, Archavlis E, Amberiadis P, et al. A prospective study comparing various anti-H. pylori treatment regimens for patients with peptic ulcer disease (PUD). Gut 1999;45 Suppl 5:A192 Abstract #P0578.

Moayyedi 1996 {published data only} Moayyedi P, Langworthy H, Shanahan K, Tompkins DS, Dixon MF, Chalmers DM, et al. Comparison of one or two weeks of lansoprazole, amoxicillin, and clarithromycin in the treatment of Helicobacter pylori. Helicobacter 1996;1(2): 71–4. Mones 1997 {published data only} Mones J, Sainz S, Sola-Vera J, Richart E, Sancho FJ, Balanzo J. Helicobacter pylori eradication with omeprazole, amoxicillin and clarithromycin: One week vs two weeks and reinfection rate at one year. Gastroenterology 1997;112 (4):A224.

Palmas 2002 {published data only} Palmas F, Pellicano R, Massimetti E, Berrutti M, Fagoonee S, Rizzetto M. Eradication of Helicobacter pylori infection with proton pump inhibitor-based triple therapy. A randomised study. Panminerva Medica 2002;44(2):145–7. Paoluzi 1998 {published data only} Paoluzi P, Rossi P, Consolazio A, Paoluzi OA, Pietroiusti A, Maggio F, et al. A single-blind, monocentric study of four treatments for H. pylori eradication: an interim report. Gastroenterology 1998;114(4 Suppl 2):A252-3. Abstract G1039. Paoluzi 2006 {published data only} Paoluzi P, Iacopini F, Crispino P, Nardi F, Bella A, Rivera M, et al. 2-week triple therapy for Helicobacter pylori infection is better than 1-week in clinical practice: a large prospective single-center randomized study. Helicobacter 2006;11(6): 562–8. Park 2009a {published and unpublished data} Park SH, Chun HJ, Choi HS, Lee KG, Kim JH, Hyun JJ, et al. The 10-day sequential therapy for Helicobacter pylori eradication in Korea: Less effective than expected. Gut 2009;58 Suppl II:A256. Abstract#P0726.


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Pellicano 2002 {published data only} Pellicano R, Palmas F, Ponzetto A, Astegiano M, Smedile A, Morgando A, et al. Decreasing eradication rate of Helicobacter pylori infection with metronidazolebased triple therapy. A randomised study. Minerva Gastroenterologica e Dietologica 2002;48(3):265–70. Pozzato 1998 {published data only} Pozzato P, Zagari M, Cardelli A, Catalano FA, Giglio A, Lami F, et al. Ranitidine bismuth citrate plus clarithromycin 7-day regimen is effective in eradicating Helicobacter pylori in patients with duodenal ulcer. Alimentary Pharmacology and Therapeutics 1998;12(5):447–51. Riquelme 2007 {published data only} Riquelme A, Soza A, Pedreros C, Bustamante A, Valenzuela F, Otarola F, et al. Optimal length of triple therapy for H pylori eradication in a population with high prevalence of infection in Chile. World Journal of Gastroenterology 2007; 13(21):2967–72. Robles-Jara 2008 {published data only} Robles-Jara C, Robles-Medranda C, Moncayo M, Landivar B, Parrales J. Is a 7-day Helicobater pylori treatment enough for eradication and inactivation of gastric inflammatory activity?. World Journal of Gastroenterology 2008;14(18): 2838–43. Sacco 2010 {published data only} Sacco F, Spezzaferro M, Amitrano M, Grossi L, Manzoli L, Marzio L. Efficacy of four different moxifloxacin-based triple therapies for first-line H. pylori treatment. Digestive and Liver Disease 2010;42(2):110–4. Savarino 1999 {published data only} Savarino V, Zentilin P, Bisso G, Pivari M, Bilardi C, Biagini R, et al. Optimal duration of therapy combining ranitidine bismuth citrate with clarithromycin and metronidazole in the eradication of Helicobacter pylori infection. Alimentary Pharmacology and Therapeutics 1999;13(1):43–7. Scaccianoce 2006 {published data only} Scaccianoce G, Hassan C, Panarese A, Piglionica D, Morini S, Zullo A. Helicobacter pylori eradication with either 7-day or 10-day triple therapies, and with a 10-day sequential regimen. Canadian Journal of Gastroenterology 2006;20(2): 113–7. Scaccianoce 2008 {published data only} Scaccianoce G, Zullo A, Hassan C, Gentili F, Cristofari F, Cardinale V, et al. Triple therapies plus different probiotics for Helicobacter pylori eradication. European Review for Medical and Pharmacological Sciences 2008;12(4):251–6. Simsek 1999 {published data only} Simsek I, Soyturk M, Akpinar H, Ellidokuz E, Topalak O, Okan E, et al. The comparison of the efficiency of the efficiency of one and two weeks lansoprazole, amoxycillin, clarithromycin (LAC) treatment protocols in the eradication of Helicobacter Pylori by using urea breath test. Gut 1999; 45 Suppl 5:A274. Abstract #P1037. Sun 2010 {published data only} Sun Q, Liang X, Zheng Q, Liu W, Xiao S, Gu W, Lu H. High efficacy of 14-day triple therapy-based, bismuth-

containing quadruple therapy for initial Helicobacter pylori eradication. Helicobacter 2010;15(3):233–8. Suriani 2008 {published data only} Suriani R, Serra A, Vernetto A, Mazzucco D, Grosso S, Morgando A, et al. Probiotic supplementation improves tolerance to H. pylori eradication therapy in dyspeptic patients: preliminary data of a multicenter, controlled, double-blind randomized pilot study. Helicobacter 2008;13 (5):470. Vakil 2004 {published data only} Vakil N, Lanza F, Schwartz H, Barth J. Seven-day therapy for Helicobacter pylori in the United States. Alimentary Pharmacology and Therapeutics 2004;20(1):99–107. Wong 2000 {published data only} Wong BC, Xiao SD, Hu FL, Qian SC, Huang NX, Li YY, et al. Comparison of lansoprazole-based triple and dual therapy for treatment of Helicobacter pylori-related duodenal ulcer: an Asian multicentre double-blind randomized placebo controlled study. Alimentary Pharmacology and Therapeutics 2000;14(2):217–24. Yang 1999 {published data only} Yang JC, Yang KC, Hsu CT, Wang CS, Kuo CF, Wang TH. A multicenter study on eradication of Helicobacter pylori infection in patients with duodenal ulcer by lansoprazoleantibiotics combined therapy. Journal of Microbiology, Immunology, and Infection 1999;32(1):1–8. Zagari 2007 {published data only} Zagari RM, Bianchi-Porro G, Fiocca R, Gasbarrini G, Roda E, Bazzoli F. Comparison of 1 and 2 weeks of omeprazole, amoxicillin and clarithromycin treatment for Helicobacter pylori eradication: the HYPER Study. Gut 2007;56(4): 475–9. Zheng 2009 {published data only} Zheng Q, Dai J, Li X, Lu H, Xiao S. Comparison of the efficacy of pantoprazole based triple therapy versus quadruple therapy in the treatment of Helicobacter pylori infection: A single-center, randomized, open and parallel-controlled study [ Chinese Journal of Gastroenterology 2009;14(1):8-11.

References to studies excluded from this review Aragona 2002 {published data only} Aragona G, Da Bo N, Anna I, Cavestro GM, Moussa AM, Iori V, et al. Lactoferrin in a 7 days triple therapy forHelicobacter Pylori eradication: results of an open randomized trial. Gut 2002;51 Suppl 3:A 109. Abstract MON-G-408. Aragona 2003a {published data only} Aragona G, di Mario F, Cavallaro LG, Cavestro GM, Iori V, Comparato G, et al. Lactoferrin in a 1-Week Triple Therapy for Eradication of H. pylori. Helicobacter 2003;8: 463. Abstract 16.06.


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Aragona 2003b {published data only} Aragona G, Dal Bo’ N, Comparato G, Leandro G, Carloni C, Liatopoulou S, et al. Lactoferrin in a one week triple therapy for eradication of H. pylori. Gastroenterology 2003; 124(4 Suppl 1):Abstract M1505. Armuzzi 2001 {published data only} Armuzzi A, Cremonini F, Ojetti V, Bartolozzi F, Canducci F, Candelli M, et al. Effect of Lactobacillus GG supplementation on antibiotic-associated gastrointestinal side effects during Helicobacter pylori eradication therapy: a pilot study. Digestion 2001;63(1):1–7. Basu 2009a {published data only} Basu PP, Rayapudi K, Pacana T, Shah NJ. A randomized open-label clinical trial with levofloxacin, omeprazole, Alinia (nitazoxanide) and doxycycline (LOAD) versus lansoprazole, amoxicillin and clarithromycin (LAC) in the treatment naive Helicobacter pylori population. American Journal of Gastroenterology 2009;104 Suppl 3:S404. Abstract 1100. Basu 2009b {published data only} Basu PP, Rayapudi K, Pacana T, Ramamurthy S. A randomized open-label clinical trial with Levofloxacin, Omeprazole, Alinia (nitazoxanide), and Doxycycline (LOAD) versus Lansoprazole, Amoxicillin and Clarithromycin (LAC) in the treatment naive Helicobacter pylori population. Gastroenterology 2009;136(5 Suppl 1): A24. Abstract 131. Bazzoli 1999 {published data only} Bazzoli F, Bianchi Porro G, Fiocca R, Gasbarrini G, Roda E, Zagari RM. Eradication of HP with omeprazole plus amoxicillin or amoxicillin and clarithromycin for 1 or 2 weeks in patients with duodenal ulcer. Gut 1999;45 Suppl 5:A6. Abstract 05.07. Bazzoli 2000a {published data only} Bazzoli F, Bianchi Porro G, Fiocca R, Gasbarrinini G, Roda E, Zagari RM. Eradication of Helicobacter pylori and ulcer healing in patients with duodenal ulcer by one-week or two week omeprazole triple therapy. Gut 2000;46 Suppl 2: Abstract TH49. Bazzoli 2000b {published data only} Bazzoli F, Bianchi Porro G, Roda E, Gasbarrini GB, Zagari RM, on behalf of the participants at the HYPER study group. Efficacy of omeprazole plus amoxicillin or amoxicillin plus clarithromycin for 1 week or 2 weeks for helicobacter pylori eradication in patients with duodenal ulcer. Gastroenterology 2000;118 Suppl 2:Abstract 2651. Bell 1995 {published data only} Bell GD, Powell KU, Burridge SM, Bowden AF, Atoyebi W, Bolton GH, et al. Rapid eradication of Helicobacter pylori infection. Alimentary Pharmacology and Therapeutics 1995; 9(1):41–6. Boudjella 2009 {published data only} Boudjella M, Matougui N, Tebaibia A, Oumnia N, Lahcene M, Mouffok F, et al. Factors influencing the efficacy of firstline treatment of H. pylori injection in Algerian patients. Helicobacter 2009;14(4):350.

Brecken 1999 {published data only} Brecken RK, Valle PC, Gangsoey Kristiansen M, Nordgaaard K, Wessel-Berg AM, Bogsrud TV. Tolerance, duration and efficacy of 5 and 7 days low-dose proton pump inhibitor triple Helicobacter pylori therapy compared to 10 days bismuth triple therapy. Scandinavian Journal of Gastroenterology. Supplement 1999;229:8. Calderon 2002 {published data only} Calderon IE, Reed G, Orozco A, Blancas JM, de Arino M, Tamayo JL, et al. Open-label, multicenter, comparative study of therapy with triple drug trial for eradication of Helicobacter pylori with sodium rabeprazole, ofloxacin and amoxicillin. Comparative trial of 7 vs. 14 days treatment. European Helicobacter Study Group. XVth International Workshop 2002; abstract book. 2002:A98. Abstract 15.33. Calvet 2000 {published data only} Calvet X, García N, López T, Gisbert JP, Gené E, Roque M. A meta-analysis of short versus long therapy with a proton pump inhibitor, clarithromycin and either metronidazole or amoxycillin for treating Helicobacter pylori infection. Alimentary Pharmacology and Therapeutics 2000;14(5): 603–9. Calvet 2001 {published data only} Calvet X, Gené E, López T, Gisbert JP. What is the optimal length of proton pump inhibitor-based triple therapies for H. pylori? A cost-effectiveness analysis. Alimentary Pharmacology and Therapeutics 2001;15(7):1067–76. Calvet 2004 {published data only} Calvet X, Helicobacter pylori working group of the Asociacion Espanola de Gastroenterologia (AEG). Randomised controlled trial comparing 7 vs. 10 days of triple therapy using rabeprazole, clarithromycin and amoxicillin for Helicobacter pylori (Hp) eradication. Preliminary results. Helicobacter 2004;9:Abstract 11.13. Calvet 2005b {published data only} Calvet X, Ducons J, Bujanda L, Bory F, Montserrat A, Gisbert JP. Seven vs. ten-day rabeprazole triple therapy for Helicobacter Pylori eradication: a multicenter, randomized trial. Gastroenterology 2005;128(4 Suppl 2):A425. Abstract T945. Cardelli 1997 {published data only} Cardelli A, Cordiano C, Giglio A, Lami F, Pilotto A, Pozzato P, et al. A new dual 7-day therapy is effective in eradicating Helicobacter pylori in duodenal ulcer patients. Gut 1997; 41 Suppl 3:Abstract P750. Castro 2001 {published data only} Castro E, Galindo E, for PANTOPYLORI. Efficacy on eradication of H. pylori with three different schedules. Gastroenterology 2001;120(5 Suppl 1):A-581. Abstract # 2952. Cerqueira 2011 {published data only} Cerqueira RM, Manso MC, Correia MR, Fernandes CD, Vilar H, Nora M, Martins P. Helicobacter pylori eradication therapy in obese patients undergoing gastric bypass surgery-fourteen days superior to seven days?. Obesity Surgery 2011; 21(9):1377–81.


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Chen 1995 {published data only} Chen TS. Tsay SH. Chang FY. Lee SD. Triple therapy for the eradication of Helicobacter pylori and reduction of duodenal ulcer relapse: comparison of 1 week and 2 week regimens and recrudescence rates over 12 months. Journal of Gastroenterology and Hepatology 1995;10(3):300–5. Chen 1996a {published data only} Chen S, Chen Z, Bei L. Omeprazole, clarithromycin and amoxicillin therapy for Helicobacter pylori infection [Chinese]. Zhonghua Nei Ke Za Zhi (National Medical Journal of China) 1996;35(12):799–802. Chen 1996b {published data only} Chen SP, Lian B, Wen SH. Triple therapy with omeprazole, clarithromycin and amoxicillin for cure of Helicobacter pylori infection. Gut 1996;39 Suppl 3:A145. Abstract # 823. Ching 1997 {published data only} Ching CK, Chan YK, Ng WC. The combination of omeprazole, amoxycillin and clarithromycin eradicates Helicobacter Pylori in 95% of cases-7 day equals 10-days therapy. Gastroenterology 1997;112 Suppl 1:A87.

Di Caro 2001b {published data only} Di Caro S, Zocco MA, Cremonini F, Armuzi A, Santarelli L, Candelli E, et al. Efficacy of 5,7 and 10 days of levofloxacinbased dual therapy for H pylori eradication. Gut 2001;49 Suppl 2:A105. Abstract 15/31. Di Caro 2001c {published data only} Di Caro S, Zocco MA, Cremonini F, Armuzzi A, Candelli M, Torre HS, et al. Lack of efficacy of a levofloxacin-based dual therapy for H. Pylori eradication. Gastroenterology 2001;120(5 Suppl 1):A581. Abstract 2953. Di Caro 2002b {published data only} Di Caro S, Zocco M, Cremonini F, Candelli M, Bartolozzi F, Armuzzi A, et al. Different schedule of levofloxacin based therapy in H. pylori infection. Journal of Gastroenterology and Hepatology 2002;17 Suppl:A234. Abstract P.B.020. Di Mario 1999 {published data only} Di Mario F, Dai Bo N, Battaglia G, Pilotto A, Franceschi M, Marin R, et al. Are 6 days of a triple clarithromycin based therapy sufficient to obtain the cure ofH. pylori infection?. Gut 1999;45 Suppl 5:A271. Abstract P1023.

Choi 2006 {published data only} Choi M, Oh JH, Kwon JH, Palk CN, Park JM, Choi YK, et al. Effect of CYP2C19 genotype on the eradication rate of Helicobacter pylori infection by pantoprazole based triple therapy in Koreans. Gut. 2006; Vol. UEGW Suppl: abstract MON-G-51.

Di Mario 2002 {published data only} Di Mario F, Aragona 1 G, Dal Bo N, Ingegnoli A, Cavestro GM, Moussa AM, et al. Potential use of lactoferrin in a 7 days triple therapy for Helicobacter pylori eradication: preliminary results. European Helicobacter Study Group. XVth International Workshop; abstract book. 2002:A98. Abstract 15.30.

Chun 2010 {published data only} Chun H, Hyun J, Park S, Keum B, Seo Y. The 10-day sequential therapy for Helicobacter pylori eradication in Korea: Less effective than expected. International Journal of Medicine 2010;40 Suppl 1:85. Abstract #69.

Di Mario 2003b {published data only} Di Mario F, Aragona G, Dal Bo N, Ingegnoli A, Cavestro GM, Moussa AM, et al. Use of lactoferrin for Helicobacter pylori eradication. Preliminary results. Journal of Clinical Gastroenterology 2003;36(5):396–8.

Daghaghzadeh 2005 {published data only} Dagagzadeh H, Emami MH, Karimi S, Esmaeili A. Oneweek versus two-week furazolidone based quadruple therapy as the first-line treatment for Helicobacter pylori Infection in Iran. Canadian Journal of Gastroenterology 2005;19 (Suppl C):R.0224.

Flores 2010 {published data only} Flores HB, Salvana A, Ang ER, Estanislao NI, Velasquez ME, Ong J, et al. Duration of proton-pump inhibitorbased triple therapy for Helicobacter pylori eradication: A meta-analysis. Gastroenterology 2010;138(5 Suppl 1):S340.

Dammann 1997 {published data only} Dammann HG, Folsch UR, Hahn EG, et al. 7 vs 14 day treatment with pantoprazole, clarithromycin and metronidazole for cure of H. pylori infection in duodenal ulcer patients. Gut 1997;41 Suppl 1:A95. Abstract 09/349. de Silva 2004 {published data only} de Silva HA, Hewavisenthi J, Pathmeswaran A, Dassanayake AS, Navaratne NM, Peiris R, et al. Comparison of one week and two weeks of triple therapy for the eradication of Helicobacter pylori in a Sri Lankan population: a randomised, controlled study. Ceylon Medical Journal 2004; 49(4):118–22. Di Caro 2001a {published data only} Di Caro S, Zocco MA, Cremonini F, Bartolozzi F, Armuzi A, Carloni E, et al. Efficacy of 5, 7, and 10 days levofloxacinbased dual therapy for H. pylori eradication. Gut 2001;49 Suppl 3:Abstract 2534.

Ford 2003 {published data only} Ford A, Moayyedi P. How can the current strategies for Helicobacter pylori eradication therapy be improved? . Canadian Journal of Gastroenterology 2003;17 Suppl B: 36B–40B. Fuccio 2007 {published data only} Fuccio L, Minardi ME, Zagari RM, Grilli D, Magrini N, Bazzoli F. Meta-analysis: duration of first-line protonpump inhibitor based triple therapy for Helicobacter pylori eradication. Annals of Internal Medicine 2007;147(8): 553–62. Gené 2006 {published data only} Gené E, Calvet X, Azagra R, Gisbert JP. Seven or ten days? Cost-effectiveness study on the duration of H. pylori treatment in primary care [Siete o diez dias? Estudio de coste–efectividad sobre la duracion del tratamiento de la infeccion por H. pylori en atencion primaria]. Atencion Primaria 2006;38(10):555–62.


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Giasi-Gonzalez 2004 {published data only} Giasi-Gonzalez E, Martínez Vázquez M, Garza-Gonzalez E, et al. Randomized controlled trial: 7 vs. 14 days of a triple therapy of amoxicillin-clarithromycin rabeprazole for the eradication of Helicobacter pylori and its correlation with the CYP2C19 genotype. Helicobacter 2004;9(5):574. Abstract 11.19.

Kamberoglou 2001 {published data only} Kamberoglou D, Polymeros D, Sanidas I, Doulgeroglou V, Savva S, Patra E, et al. Comparison of 1-week vs. 2- or 4-week therapy regimens with ranitidine bismuth citrate plus two antibiotics for Helicobacter pylori eradication. Alimentary Pharmacology and Therapeutics 2001;15(9): 1493–7.

Gisbert 2005b {published data only} Gisbert JP, Dominguez-Munoz A, Dominguez-Martin A, Gisbert JL, Marcos S, Pajares JM. Esomeprazole-based therapy in Helicobacter pylori eradication: Any effect by increasing the dose of esomeprazole or prolonging the treatment?. Helicobacter 2005;10(5):530. Abstract 11.07.

Kang 2000b {published data only} Kang CD, Chun HJ, Hur BW, Jeen YT, Lee HS, Song CW, et al. Significance of pretreatment 13CO2 as predictor of success for H. pylori eradication. Gastroenterology 2000;118 Suppl 2:Abstract 4715.

Greenberg 2011 {published data only} Greenberg ER, Anderson GL, Morgan DR, Torres J, Chey WD, Bravo LE, et al. 14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial. Lancet 2011;378(9790):507–14. Habu 1997 {published data only} Habu Y, Mizuno S, Hirano S, Kiyota K, Hayakumo T, Inokuchi H, et al. Randomized comparison of 1 week and 2 weeks of omeprazole, amoxicillin and clarithromycin treatment for the cure of Helicobacter pylori infection in gastric and duodenal ulcer patients. Gastroenterology 1997; 112 Suppl:A136. Hasan 2010 {published data only} Hasan SR, Vahid V, Reza PM, Roham SR. Short-duration furazolidone therapy in combination with amoxicillin, bismuth subcitrate, and omeprazole for eradication of Helicobacter pylori. Saudi Journal of Gastroenterology 2010; 16(1):14–8. Herba 2009 {published data only} Herba K, Szilagyi A, Fallone C. Initial therapy for Helicobacter pylori eradication in a Canadian real life setting: An interim analysis comparing 7 and 14 day triple therapy regimens. Canadian Journal of Gastroenterology 2009;23: Abstract #95. Iwasaki 1997 {published data only} Iwasaki A, Nakajima N. Ushiyama K, et al. Study of the usefulness of measurement of serum pepsinogen in eradication therapy of Helicobacter pylori. Gastroenterology 1997;112 Suppl 1:A159. Abstract #G0625. Jung 2006 {published data only} Jung S, Lee S, Koo J, Yim H, Lee H, Choi J, et al. Effecacy of proton pump inhibitor-based triple therapy for eradicating Helicobacter pylori in patients with chronic liver disease and peptic ulcer. Helicobacter 2006;11:414. Abstract 17.06. Jung 2008 {published data only} Jung HS, Shim KN, Kang MJ, Jung JM, Ha CY, Na YJ. Comparison of the H. pylori eradication rate according to the duration of first-line triple therapy: a meta-analysis. Gastroenterology 2008;134(4 Suppl 1):P-268. Abstract # T1647.

Karatapanis 2000 {published data only} Karatapanis S, Georgopoulos S, Papakonstantinou L, Papamarkos D, Mentis A, Artikis V. Rabeprazole 7-days vs rabeprazole 10-days triple therapy in the eradication of H. pylori infection - A randomized study. Gut 2000;47 Suppl 1:A107. Abstract 15/35. Karatapanis 2005 {published data only} Karatapanis S, Georgopoulos S, Skorda L, Papantoniou N, Komnianides K, Lisgos P, et al. Rabeprazole 7-days vs. rabeprazole 10-days vs. rabeprazole 14 days triple therapy in the eradication of H. pylori infection- a randomized study. Gastroenterology 2005;128(4 Suppl 2):A-428. Abstract T958. Karatapanis 2007 {published data only} Karatapanis S, Georgopoulos S, Skorda L, Papantoniou N, Mathaios I, Lisgos P, et al. Triple regimen of variable duration (7 days vs 10 days vs 14 days), based on rabeprazole, in the eradication of Helicobacter pylori. A randomized study. Gut 2007;56 (Suppl 3):Abstract #MonG-59. Katicic 1996 {published data only} Katicic M, Presecki V, Marusic M, Prskalo M, Ticak B, Sabaric B, et al. Eradication of H. pylori infection in peptic ulcers with four different drug regimens. Gut 1996;39 Suppl 3:A144. Abstract # 817. Katicic 2006 {published data only} Katicic M, Ticak M, Prskalo M, Naumovski-Mihalic S, Fillipec-Kanizaj T, Skurla B, et al. Eradication of Helicobacter pylori infection with two triple-therapy regimes of 7, 10, and 14 days; four years experience. Helicobacter 2006;11:386. Abstract # 11.05. Khu 2010 {published data only} Khu JV, Lim LL. Helicobacter pylori eradication regimens: Is there a difference?. Journal of Pharmacy Practice and Research 2010;40(3):194–8. Kim 2001 {published data only} Kim YB, Chun HJ, JeenYT, Lee JW, Song CW. H. pylori eradication rate according to the duration of triple therapy in Korea: meta-analysis evaluation of H. pylori trial. Gastroenterology 2001;120(5 Suppl 1):A-583. Abstract# 2965. Knigge 1998 {published data only} Knigge, K, Kelly, C, Fennerty, MB, Peterson WK. A multicenter randomized trial with twice daily ranitidine


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bismuth-citrate (R), metronidazole (M) and tetracycline (T) for 7 or 10 days for eradication of H-pylori infection. Gastroenterology 1998;114(4 Suppl 2):Abstract G0736. Krause 1997 {published data only} Krause R, Pruitt R, Lukasik N, Thomas J, Fennerty B. 10 vs 14 day triple therapy with lansoprazole (Prevacid), amoxicillin, and clarithromycin in the eradication of Helicobacter pylori (Hp). Gut 1997;41 Suppl:A101. Abstract 09/373. Labenz 1993 {published data only} Labenz J, Gyenes E, Ruhl GH, Borsch G. Omeprazole plus amoxicillin: efficacy of various treatment regimens to eradicate Helicobacter pylori. American Journal of Gastroenterology 1993;88(4):491–5. Lamouliatte 1998 {published data only} Lamouliatte H, Forestier S, Perie F. Lansoprazole (Lanso) 30 mg or 60 mg combined with two antibiotics (AMOX) and clarithromycin (Clari) to eradicate Helicobacter pylori (H. pylori). Gut 1998;43 Suppl 2:A80-1. Abstract 10/275. Lamouliatte 2000 {published data only} Lamouliatte H, Perie F, Joubert-Collin M. Lansoprazole 30 mg or 60 mg combined with two antibiotics (amoxicillin and clarithromycin) to eradicate Helicobacter pylori in patients with duodenal ulcers [French]. Gastroenterologie Clinique et Biologique 2000;24(5):495–500. Lanza 2002 {published data only} Lanza F, Kovacs T, Hahne W, Barth J, Sontag S. Rabeprazole-based triple therapy is safe and well tolerated in Helicobacter pylori eradication: findings from a large US multicenter trial. American Journal of Gastroenterology 2002; 97 Suppl 9:S24. Abstract 71. Lee 1997 {published data only} Lee SW, Jin YT, Chun HJ, Um SH, Kim CD, Ryu HS, Hyun JH. The patients’ compliance of anti-Helicobacter pylori triple regimen with low dose clarithromycin in Korea. Gut 1997;41 (UEGW Suppl):Abstract P745. Lee 1998 {published data only} Lee KH, Kim NY, Ko YH, et al. Triple therapy for eradication of H. pylori in patients with peptic ulcer [Korean]. Korean Journal of Gastroenterology 1998;31(5): 605–14. Lee 2004b {published data only} Lee S, Keum B, Chung R, Lee H, Um S, Choi J, et al. Comparison of Helicobacter pylori eradication rate according to proton pump inhibitor-based triple therapy: omeprazole, rabeprazole, esomeprazole and lansoprazole. Helicobacter 2004;9:579. Abstract 11.34. Lee 2006 {published data only} Lee EJ, Gham CW, Park TW, et al. The effect of Helicobacter pylori eradication on the improvement of the symptoms in patients with functional dyspepsia and peptic ulcer disease. [Korean]. Korean Journal of Medicine 2006;71 (2):141–8. Liao 2002 {published data only} Liao CC, Lee CL, Lee HY, Wu CH, Chen TK, Tu TC, et al. Efficacy of different therapies for Helicobacter pylori

eradication pylori eradication: A 5-year experience in a single center. American Journal of Gastroenterology 2002;97 Suppl:S245. Abstract 748. Lopez-Roman 2011 {published data only} Lopez-Roman O, Warrington E, Cruz-Correa MR, Toro DH. 10-Day and 14-day sequential therapy vs. standard triple therapy for helicobacter pylori infection in a Puerto Rican treatment-naive population: An interim analysis. Gastroenterology 2011;140(5 Suppl 1):S149. Maconi 1998 {published data only} Maconi G, Imbesi V, Lazzaroni M, Bargiggia S, DiPidtro C, Morelli P, et al. One vs two week regimens of lansoprazole (L), amoxicillin (A), and clarithromycin (C) for duodenal ulcer (DU) healing and H. pylori (Hp) eradication. Digestion 1998;59 Suppl 3:419. Abstract ExhB3164. Maconi 1999 {published data only} Maconi G, Imbesi V, Russo A, et al. Prolongation of a PPIbased triple therapy from one to two weeks is of benefit to patients with high H. pylori density and current smokers. Gut 1999;45 Suppl V:A5. Abstract 05.03. Makarenka 2004 {published data only} Makarenka AU, Pimanau SI. Results of eradication with classical triple and furazolidone-based regimens in patients with high bacterial density of Helicobacter pylori. Helicobacter 2004;9(5):580. Abstract 11.37. Makarenka 2005 {published data only} Makarenka AV, Pimanov SI. Eradication rate after randomized treatment in a population with high prevalence of Helicobacter pylori infection. Helicobacter. Helicobacter 2005;10:535. Abstract #11.22. Matougui 2009 {published data only} Matougui N, Boudjella ML, Mouffok F, Bouhadef A, Guechi Z, Bouzid K, et al. H. pylori eradication by four triple therapies: Randomized study in double-blind. Helicobacter 2009;14 (4):403. Miwa 1998 {published data only} Miwa H, Ohkura R, Murai T, Nagahara A, Yamada T, Ogihara T, et al. Effectiveness of omeprazole-amoxicillinclarithromycin (OAC) therapy for Helicobacter pylori infection in a Japanese population. Helicobacter 1998;3(2): 132–8. Moayyedi 1995 {published data only} Moayyedi P, Tompkins DS, Shanaghan K, Langworthy H, Axon ATR. Comparison of one and 2 weeks of lansoprazole, amoxycillin and clarithromycin in eradicating H.pylori. Gut 1995;37 Suppl 2:A7. Abstract W25. Nishikawa 1999 {published data only} Nishikawa K, Sugiyama T, Ishizuka J, Kudo T, Komatsu Y, Katagiri M, et al. Eradication of Helicobacter pylori using 30 mg or 60 mg lansoprazole combined with amoxicillin and metronidazole: one and two weeks of a new triple therapy. Journal of Gastroenterology 1999;34 Suppl XI: 72–5. Ogura 2000 {published data only} Ogura K, Yoshida H, Maeda S, Yamaji Y, Mitsuno Y, Akanuma M, et al. Triple therapy with faropenem against


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drug-resistant helicobacter pylori. Gastroenterology 2000; 118 Suppl 2:Abstract #2679. Ogura 2007 {published data only} Ogura K, Mitsuno Y, Maeda S, Hirata Y, Yanai A, Shibata W, et al. Efficacy and safety of faropenem in eradication therapy of Helicobacter pylori. Helicobacter 2007;12(6): 618–22. Oh 2006 {published data only} Oh JH, Choi M, Dong M, Park J, Kwon J, Pail C, et al. Effect of CYP2C19 genotype on the eradication rate of Helicobacter pylori infection by pantoprazole based triple therapy in Koreans. Gut 2006;55 (UEGW suppl):Abstract MON-G-51. Oqura 2007 {published data only} Ogura K, Mitsuno Y, Maeda S, Hirata Y, Yanai A, Shibata W, et al. Efficacy and safety of faropenem in eradication therapy of Helicobacter pylori. Helicobacter 2007;12(6): 618–22. Paoluzi 2001 {published data only} Paoluzi P, Lacopini F, Consolazio A, et al. Two week PPIbased triple therapy with amoxycillin and clarithromycin has a higher efficacy in Helicobacter pylori eradication. Gut 2001;49 Suppl 3:A 2545. Park 2009b {published data only} Park SH, Chun HJ, Kim ES, Park SC, Jung ES, Lee SD, et al. The 10-day sequential therapy for Helicobacter pylori eradication in Korea: Less effective than expected. Gastroenterology 2009;136(5 Suppl 1):A399-40. Abstract# M1053. Pimanov 2005 {published data only} Pimanov SI, Makarenka AV, Matveenko ME. Eradication and reinfection rates after randomized treatment in a population with high prevalence of Helicobacter pylori infection. Gut 2005;54 Suppl 7:A127. Abstract. MONG-214. Rodionoff 1990 {published data only} Rodionoff P, Hyland L, Ostapowicz N, et al. Triple therapy for Helicobacter pylori eradication: 1, 2 or 4 weeks?. Sydney, Australia: World Congress of Gastroenterology. August, 1990:Abstract PP938. Rodríguez 2003 {published data only} Rodríguez W, Pareja Cruz A, Yushimito L, Ramírez Ramos A, Gilman RH, Watanabe Yamamoto J, et al. Omeprazole, amoxicillin and clarithromycin in the treatment of helicobacter pylori, in 7 and 10-day regimens [Tratamiento del Helicobacter Pylori con Omeprazole, Amoxicilina y Clarithromicina en esquemas de 7 y 10 dias]. Revista Gastroenterología del Perú 2003;23(3):177–83. Rodríguez Téllez 1999 {published data only} Rodríguez Téllez M, Valenzuela Barranco M, Caballero Plasencia A, Martín Ruiz J, López-Andrade A, Carmona Soria I, et al. Morphometric estimation of acid output in duodenal ulcer associated with Helicobacter pylori infection. Revista Española de Enfermedades de Digestivas 1999;91(8):549–58.

Rogha 2009 {published data only} Rogha M, Pourmoghaddas Z, Rezaee M, Shirneshan K, Shahi Z. Azithromycin effect on helicobacter pylori eradication: double blind randomized clinical trial. Hepatogastroenterology 2009;56(91-92):722–4. Sacco 2008 {published data only} Sacco F, Spezzaferro M, Serio M, Amitrano M, Cerasa B, Grossi L, Marzio L. Effect of three different regimens with esomeprazole, amoxicillin, and moxifloxacin in the treatment of primary H. pylori Infection. Gastroenterology 2008;134(4 Suppl):A24. Abstract 140. Salandin 1995 {published data only} Salandin S, Battaglia G, Dal Bo N, Lecis PE, Pilotto A, Ferrana M, et al. Clarithromycin for the cure of H.pylori infection: one or 2 weeks of treatment?. Gastroenterology 1995;108:A207. Schwartz 2002 {published data only} Schwartz H, Monkemuller K, Perdomo C, Barth J, Stanton D. Helicobacter pylori eradication with rabeprazole-based triple therapy: findings in 803 patients with antibioticsensitive and resistant strains. American Journal of Gastroenterology 2002;97(9 Suppl):S21. Abstract 63. Sharma 2002 {published data only} Sharma MP, Chaudhary A, Ahuja V. Three weeks triple therapy is better than two or one week therapy for eradication of Helicobacter pylori in peptic ulcer disease. Journal of Gastroenterology and Hepatology 2002;17 Suppl: A24. Abstract P.B.005. Simsek 2000 {published data only} Simsek I. Reinfection rate of Helicobacter Pylori infection after one and two weeks triple. A 17-month follow-up study. Gut 2000;47 Suppl 3:A103. Abstract P296. Utzon 1994 {published data only} Utzon P, Aabakken L, Sandstad O, Guldvog I, Skar V. Eradication of helicobacter pylori with 10 or 14 days of bismuth triple regimes. Gut 1994;35 Suppl IV:A150. Uygun 1999 {published data only} Uygun A, Ates Y, Erdil A, Kadayifci A, Cetin C, Gulsen M, et al. Efficacy of omeprazole plus two antimicrobials for the eradication of Helicobacter pylori in a Turkish population. Clinical Therapeutics 1999;21(9):1539–48. Vakil 2002a {published data only} Vakil N, Schwartz H, Lanza F, Nardi L, Hahne W, Barth J. A prospective, controlled, randomised trial of 3-,7- and 10day rabeprazole based triple therapy for H. pylori eradication in the USA. Gastroenterology 2002;122(4 Suppl):A 65. Abstract 551. Vakil 2002b {published data only} Vakil N, Schwarz H, Lanza F, Hahne W, Barth J. Seven-day rabeprazole-based triple therapy for H. pylori eradication is as effective as 10-day omeprazole-based triple therapy. European Helicobacter Study Group. XVth International Workshop 2002. Abstract book. 2002:A95. Abstract 15.19.


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Vakil 2002c {published data only} Vakil N, Kovacs T, Ignatowitz W, Hahne W, Barth J. Presence or absence of peptic ulcer disease does not affect H. pylori eradication rates with rabeprazole-based triple therapy. European Helicobacter Study Group. XVth International Workshop 2002. Abstract book. 2002:A95. Abstract 15.09. Vakil 2002d {published data only} Vakil N, Kovacs T, Barth J. Antibiotic resistance accounts for only one third of treatment failures with triple therapy for H.pylori. Gut 2002;51 Suppl 3:A215. Abstract TUEG-488. Vakil 2002e {published data only} Vakil N, Schwartz H, Lanza F, Barth J. Safety and tolerability of rabeprazole-based triple therapy for Helicobacter eradication in a large US trial. Gut 2002;51 Suppl 3:A110. Abstract MON-G-412. Vakil 2002f {published data only} Vakil N, Jayanty V, Stanton D, Perdomo C, Hahne W, Barth J. Antibiotic sensitivity in a large US multicenter trial of rabeprazole-based triple therapy for H. pylori eradication. Gastroenterology 2002;122(4 Suppl 1):A9. Abstract 63. Vakil 2002g {published data only} Vakil N, Schwartz H, Perdomo C, Barth J, Sontag S. Racial demographics do not affect efficacy of rabeprazole-based triple therapy for Helicobacter pylori eradication. American Journal of Gastroenterology 2002;97(9 Suppl):S17. Abstract 50. Vakil 2002h {published data only} Vakil N, Stanton D, Hahne W, Barth J, Kovacs T. Consistent Helicobacter pylori eradication rates with rabeprazole-based triple therapy across demographic subgroups. American Journal of Gastroenterology 2002;97(9 Suppl):S21. Abstract 62. Vakil 2003a {published data only} Vakil N, Perdomo C, Barth J, et al. Clarithromycin resistance and H. pylori eradication rates in US racial groups with rabeprazole-based triple therapy. Gastroenterology 2003;123(4 Suppl 1):Abstract M1495. Vakil 2003b {published data only} Vakil N, Perdomo C, Barth J. Density of Helicobacter pylori (Hp) organisms does not affect eradication rates in peptic ulcer disease (PUD) and non-peptic ulcer disease (NPUD). Gastroenterology 2003;123(4 Suppl 1):Abstract S1244. Vakil 2003c {published data only} Vakil N, Perdomo C, Barth J. The effect of gastritis on Helicobacter pylori (Hp) eradication rates with triple therapy. Gastroenterology 2003;123(4 Suppl 1):Abstract 771. Xiang 2007 {published data only} Xiang L. Wen FQ. Zuo WH. Tang Y. Different courses of esomeprazole-based triple therapy for Helicobactor pylori infection in children. Zhongguo Dangdai Erke Zazhi. (Chinese Journal of Contemporary Pediatrics) 2007;9(3):205–6. [http://en.cnki.com.cn/Article˙en/ CJFDTOTAL–DDKZ200703005.htm]

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References to studies awaiting assessment Chen 2013 {published data only} Chen W, Zhang GY, Zeng Y, Li Q, Xu MH, Liu T. Furazolidone-based quadruple therapy as firstline treatment for Helicobacter pylori infection [ ]. World Chinese Journal of Digestology 2013;21(14):1366–71. Choi 2012 {published data only} Choi HS, Chun HJ, Park SH, Keum B, Seo YS, Kim YS, et al. Comparison of sequential and 7-, 10-, 14-d triple therapy for Helicobacter pylori infection. World Journal of Gastroenterology 2012;18(19):2377–82. Fallone 2013 {published data only} Fallone CA, Barkun AN, Szilagyi A, Herba KM, Sewitch M, Martel M, et al. Prolonged treatment duration is required for successful Helicobacter pylori eradication with proton pump inhibitor triple therapy in Canada. Canadian Journal of Gastroenterology 2013;27(7):397–402. Konorev 2012 {published data only} Konorev MR. Use of the immunopotentiator N-acetylglucosamine-N-acetylmuramyl dipeptide during triple antiHelicobacter pylori therapy. Terapevticheskii Arkhiv 2012;84 (12):66–70. Lv 2013 {published data only} Lv N, Xie Y, Chen Y, Wang J, Liu W, Zhang Z, et al. Furazolidone-based triple and quadruple eradication therapy for H. pylori infection. Journal of Gastroenterology and Hepatology. 2013; Vol. 28 (Suppl 3):1-22. Abastract 00029. Prasertpetmanee 2013 {published data only} Prasertpetmanee S, Mahachai V, Vilaichone R. Reliable efficacy of 14-day high dose PPI triple therapy for helicobacter pylori eradication independent effect of CYP2C19 genotype and high prevalence of metronidazole resistance in Thailand. Helicobacter. 2012; Vol. 17:99. Prasertpetmanee S, Mahachai V, Vilaichone RK. High efficacy of 14-day high dose PPI triple therapy for H. pylori eradication independent effect of CYP2C19 genotype in Thailand. Journal of Gastroenterology and Hepatology. 2012; Vol. 27:61. Prasertpetmanee S, Mahachai V, Vilaichone RK. Improved efficacy of PPI-amoxicillin-clarithromycin triple therapy for H. Pylori eradication in low clarithromycin resistance areas


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CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Antelo 2001 Methods

Single centre; Single-blind RCT.

Participants

Country: Argentina. 120 subjects with PUD or FD (duodenitis or gastritis or normal mucosal) and H. pylori infection (by RUT and histology). 80 patients were included in this systematic review

Interventions

Omeprazole 20mg, amoxicillin 1g and clarithromycin 500mg bid for 1 week or 2 weeks, the third group received OCM for 1 week. 40 patients each group. Omeprazole 20mg od post-treatment for up to 4 weeks

Outcomes

H. pylori eradication confirmed by UBT 4 weeks after completion of treatment, primary resistance to antibiotics

Notes

120 patients with positive RUT were randomised but only 113 confirmed by histology after were included in authors’ ITT analysis. We used randomised sample as the ITT sample. Authors’ defined ITT was used in sensitivity analysis. Adverse events were reported in total, no raw data available for each group. The primary resistance rate in this study was: 0% to amoxacillin, 0% to clarithromycin, 20% to metronidazole

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

“randomisation used table of numbers”

Allocation concealment (selection bias)

No detail information was provided

Unclear risk

Blinding of participants and personnel Unclear risk (performance bias) All outcomes

“single blinded” but no detail information was provided for which party was blinded

Blinding of outcome assessment (detection Unclear risk bias) All outcomes

No detail information was provided

Incomplete outcome data (attrition bias) Eradication

Eradication provided in ITT (authors’ definition) . 80 patients were randomised for the two eligible arms, authors’ ITT only included 78 patients how had histology (39 vs 39). We used randomised sample as the ITT sample. Authors’ PP sample was 103 for all three groups. It is not clear how many drop out or stopped due to adverse events or other reasons in the two eligible groups. Since the the drop out (1 vs

Low risk


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Antelo 2001

(Continued)

1) was balanced between the two arms, it is unlikely have impact on eradication effect estimate Incomplete outcome data (attrition bias) Adverse Event

Unclear risk

Adverse events were reported for each group in authors’ ITT sample. In total, 10 patients did not complete treatment or stopped treatment due to adverse events. However, It is not clear how many stopped due to adverse events in the two eligible groups. It is not clear the impact of dropping out on the adverse events


Low risk

Reported all expected outcomes including those were pre-specified

Other bias

Low risk

The study appears to be free of other sources of bias.

Aydin 2007 Methods

Single-centre RCT

Participants

Country: Turkey. 80 dyspepsia patients (with either DU or gastritis), and H. pylori infection (determined by histology and RUT)

Interventions

Pantoprazole 40mg bid, amoxicillin 1g bid and clarithromycin 500mg bid, for 7 or 14 days

Outcomes

H. pylori eradication 4 weeks after completion of therapy, assessed by RUT and histology, impact of clarithromycin resistance on H. pylori eradication rate, DU healing rate; adverse events.

Notes

Author’s ITT sample excluded 7 patients that without DNA results from the randomised patients. We used randomised sample as ITT sample. Sensitivity analysis by using author’ defined ITT analysis. Clarithromycin resistance in this study was 48.0% (35/73)

Risk of bias Bias



Random sequence generation (selection Unclear risk bias)

“randomised to”, no detail information was provided.


Unclear risk

No information was provided




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Aydin 2007

(Continued)




Low risk

Reported eradication rated in ITT and PP sample, however, the authors’ ITT excluded patients without DNA data (4 vs 3) . We calculated the eradication using the randomised sample as ITT, and used authors’ ITT sample in the sensitivity analysis. Since the patiens without DNA data was balanced between two groups, it is unlikely have impact on the eradication effect estimate

Incomplete outcome data (attrition bias) Adverse Event

Unclear risk

Adverse events were reported in PP sample (excluded unsuccessful DNA or lost to follow up), it not clear whether the excluded patients had adverse events


Low risk


Other bias

Low risk


Bago 2010 Methods

Single-centre, open, RCT

Participants

Country: Croatia. 150 patients with FD and H. pylori infection (determined by RUT, history and culture, 2 of the 3 tests must be positive)

Interventions

Lansoprazole 30mg + amoxacillin 1g + moxifloxacin 200mg, twice daily, for 7 days or 10 days

Outcomes

H. pylori eradication 4-6 weeks after completion of therapy, assessed by RUT, history and culture, all three tests must be negative). If one test suggested persistence of H. pylori a Curea test was performed.The impact of moxifloxacin resistance on H. pylori eradication was also assessed.

Notes

If one test suggested persistence of H. pylori a C- urea test was performed. Not clear how this data was used. In this study population, 6% of H. pylori stains were primary resistant to moxifloxacin, none of the stains was resistant to amoxicillin

Risk of bias Bias




“patients were distributed randomly”, no further details on randomisation method


No information was provided.

Unclear risk


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Bago 2010

(Continued)

Blinding of participants and personnel High risk (performance bias) All outcomes

“open, randomised, comparative clinical trial with parallel groups”. Patients and physicians were not blinded

Blinding of outcome assessment (detection Low risk bias) All outcomes

Endoscopist at second endoscopy were not aware of the H. pylori culture results, Microbiologist and the pathologist were blinded to the treatment regimens


Low risk

“All the patients were included in the ITT analysis.” H. pylori eradication rate reported in both ITT and PP sample. Reasons for 12 patients that did not complete the study were given. One patient lost to follow up


Low risk

Details for adverse events were reported in table 4.


Low risk

Reported all expected outcomes including those were prespecified

Other bias

Low risk


Basu 2011 Methods


Participants

Country: USA. 270 patients with dyspeptic symptoms undergoing upper endoscopy, have had H. pylori-induced gastritis confirmed by endoscopy four-quadrant stomach biopsy; and monoclonal stool antigen testing. 180 patients were included in this systematic review

Interventions

LOAD: Levofloxacin 250mg with breakfast + omeprazole 40mg before breakfast + nitazoxanide 500mg bid with meals + doxycycline 100mg at dinner, for 7 days or 10 days; LAC (lansoprazole 30mg + amoxicillin 1g + clarithromycin 500mg bid) for 10 days. 90 patients per group

Outcomes

H. pylori eradication assessed by stool antigen testing at least 4 weeks after cessation of treatment. H. pylori recurrence after one year by UBT and stool antigen. Compliance and adverse events

Notes

It is not clear the H. pylori diagnosis method in regards to ”biopsy“, we presume it was histology + stool antigen. Suspicous study, test 2 weeks after treatment in two abstracts (Basu 2009a, Basu 2009b) but 4 weeks after treatment in the full publication. The authors replied our inquires (Yuan 2012) that the study protocol was changed and some patients who were assessed after 2 weeks were re-assessed for H. pylori eradications (Basu 2012). Adverse events, Discontinued patients, recurrence, for LOAD 7 and LOAD 10 were combined in the report. This study was excluded in the sensitivity analysis

Risk of bias Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Basu 2011

(Continued)

Bias




“Randomization was performed in blocks of three, where the assignment of treatment was drawn in a blinded manner from an envelope”


“Randomization was performed in blocks of three, where the assignment of treatment was drawn in a blinded manner from an envelope” We presume the envelopes were in sequential number and opaque

Low risk


Open-label trial, patients were not blinded.


Open-label study. However, it is unclear whether the outcome assessors (eg lab technicians) for H. pylori eradication were aware of the treatment patients received. The assessment for H. pylori eradication is unlikely to have been impacted by the open-label design


Low risk

Eradication rate reported for ITT and PP sample. Reasons for discontinued therapy were given


Unclear risk

Although adverse events were reported for all randomised patients, adverse events and discontinued treatment were combined reported for LOAD7 and LOAD10 group, although the combined analysis was not planned. Based on the information combined with the information provided by the abstracts, 5 patients had GI distress in LOAD-10 vs 1 in LOAD-7 group, but we could not know the adverse event data for LOAD-7 and LOAD-10 group, respectively


High risk

Adverse events and discontinued treatment were combined reported for LOAD7 and LOAD10 group, although the combined analysis was not planned. Compliance was a secondary outcome, however, the definition was not stated, we assume it referred to patients who completed the treatment

Other bias

High risk

Some some inconsistencies between the full publication and the published abstracts was found, especially for the time of H. pylori eradication test. The authors replied our inquires that the study protocol was changed and some patients who were assessed after 2 weeks were re-assessed for H. pylori eradications (Basu 2012).


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Berrutti 2008 Methods


Participants

Country: Italy. 171 H. pylori subjects in who indications were as recommended by the Maastricht 2-2000 consensus. H. pylori infection was confirmed by ¹³C-UBT, histology was performed when an endoscopic examination was judged necessary

Interventions

1. PPI standard dose plus metronidazole 250mg qid, amoxicillin 1g bid; 2. PPI standard dose plus tinidazole 500mg bid, amoxicillin 1g bid, for 7, 10, or 14 days

Outcomes

H. pylori eradication assessed by ¹³C-UBT one month after suspension of treatment

Notes

Information such as eradication rate in ITT sample, adverse event in each group, randomisation method, was not reported in the text, but we contacted the author and obtained information. Type of PPI was not clear

Risk of bias Bias




Did not report the detail for “randomized study”, we then contacted authors, replied: “randomized was performed by a 6-block, centralized randomization list”


Did not report the detail in the paper, contact authors, replied “the trialists were not aware of the allocation of each participant before they were entered the trial, an MD not included as trialist manage the list”

Low risk


“open study”, no patients or physicians were blinded.


Open study. However, it is unclear whether the outcome assessors (eg lab technicians) for H. pylori eradication were aware of the treatment patients received. The assessment for H. pylori eradication is unlikely to have been impacted by the open-label design


Low risk

Eradication was reported in PP sample, we contacted the author and received eradication data for ITT sample. Therefore, it is considered as low risk for incomplete outcome data


Low risk

Did not report detail for adverse even in the paper, we contacted the authors and obtained the data


Low risk



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Berrutti 2008

(Continued)

Other bias

Unclear risk

The authors stated in the method that they exclude patients with poor compliance patients, unknown post-treatment H. pylori status, or protocol deviations from the ITT and PP analysis. Finally, all 3 excluded patients were those discontinued treatment due to adverse events. It is unclear whether the exclusion criteria was planned before the study

Bhasin 2000 Methods

Single-centre RCT

Participants

Country: India. 46 patients with upper GI symptoms (had PUD or duodenitis or gastritis or normal mucosal) and H. pylori infection confirmed by RUT and histology

Interventions

Lansoprazole 30mg od, clarithromycin 250 mg bid and amoxicillin 500mg tid for 1 or 2 weeks

Outcomes

H. pylori eradication 4 weeks after completion treatment confirmed by RUT and histology. Advserse events. healing of gastritis, duodenitis and GU

Notes

Low dose regimen

Risk of bias Bias




“randomly selected”, no detail information.


Unclear risk







Low risk

No patients withdrew. Eradication reported in ITT sample.


Low risk

No patient withdrew. Adverse events were reported.


Low risk



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Bhasin 2000

(Continued)

Other bias

Low risk


Bosques-Padilla 2004 Methods

Mexican, multicenter, open, RCT

Participants

Country: Mexico. 76 patients with dyspeptic symptoms (74 FD, 2 DU) and H. pylori infection (assessed by RUT and histology)

Interventions

Rabeprazole 20mg bid, ofloxacin 400mg bid and amoxicillin 1g bid for 1 or 2 weeks

Outcomes

H. pylori eradication confirmed by UBT 4 weeks after completion of treatment

Notes

Ofloxacin was 400mg bid in abstract but 400mg od in the text (contacted authors no reply)

Risk of bias Bias




”randomized, multicentre study“, no detail information was provided


No detail information was provided.

Unclear risk


Open trial. No party ws blinded.


Open study. However, it is unclear whether the outcome assessors (eg. lab technicians) for H. pylori eradication were aware of the treatment patients received. The assessment for H. pylori eradication is unlikely to have been impacted by the open-label design


Low risk

Eradication rate was reported in ITT sample and PP sample.


Unclear risk

Two patients stopped treatment due to adverse events, one withdrawn consent. Adverse events reported in event numbers. However, it is not known how many patients had adverse event


Low risk



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Bosques-Padilla 2004

(Continued)

Other bias

Low risk


Calvet 2005a Methods

Multicentre, open, RCT

Participants

Country: Spain. 458 H. pylori positive patients (by histology or RUT or UBT) with PUD (66.2%) or FD

Interventions

Rabeprazole 20mg bid, clarithromycin 500mg bid and amoxicillin 1g bid for 7 days or 10 days. Ranitidine 300mg od was indicated after treatment in patients with bleeding history (32.8%) until cure of H. pylori was confirmed at the first control.

Outcomes

H. pylori eradication after at least 8 weeks determined by histology (5%) or UBT (95%) , eradication rate for PUD and FD subgroup. Adverse events

Notes Risk of bias Bias




A random number generator was used.


”Closed envelopes produced using a random number generator were sent to participating centers“. Although is not clear whether envelopes were in sequence or opaque, the risk is likely low because the randomisation list was applied to different centre

Low risk


”No blinding method was used“.


”the personnel performing the post-eradication evaluation did not know the treatment received by the patient“


Low risk

Eradication was reported both in ITT and in PP sample. CONSORT flow diagram was present. 23 patients lost to follow up in both groups


Unclear risk

CONSORT flow diagram was present. 23 patients were lost of follow up in both groups. Although total patient numbers with adverse events were reported, it is not known how many of those who lost to follow up due to adverse events


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Calvet 2005a

(Continued)


Low risk


Other bias

Low risk


Chaudhary 2004 Methods


Participants

Country: India. 64 active DU patients with H. pylori infection (by UBT and RUT)

Interventions

Randomized to: lansoprazole 30mg bid, amoxicillin 1g bid and tinidazole 500mg bid for 1 week (n=21), 2 week (n=20), or 3 weeks (n=23)

Outcomes

H. pylori eradication 4 weeks after completion of therapy confirmed by UBT and RUT. Ulcer healing, adverse events





”randomized trial“, no detail information was provided.


No detail information was given.

Unclear risk


Open trial, no participants or personnel were blinded.




Low risk

All patients had regular follow-up and there were no dropouts. Eradication was reported in ITT sample


Unclear risk

Adverse events reported as event numbers, it is not clear how many patients had more than one event, so we could not analysis the number of patients with adverse events


85

Chaudhary 2004

(Continued)


Unclear risk

Assessed ”relief of symptoms“ but did not report this outcome in the results. However, this outcome is not the interested outcome in this review

Other bias

Low risk


Chew 1994 Methods

Single-centre RCT

Participants

Country: Canada. 40 patients with H. pylori gastritis and DU; and 24 patients with H. pylori gastritis but without DU. H. pylori infection determined by histology

Interventions

Omeprazole 60mg bid and clarithromycin 500mg bid for 1 (n=33) or 2 weeks (n=31). Randomization was performed within DU patients and within gastritis patients

Outcomes

H. pylori eradication after 5 weeks determined by histology

Notes

This study was to designed to use the highest recorded dose of omeprazole used in dual therapy

Risk of bias Bias




”randomised to“, conference proceeding, no detail information was provided


Unclear risk

Conference proceeding, no detail information was provided.






Unclear risk

Eradication reported in ITT sample. Conference proceeding, no detail information was provided for lost to follow up or drop outs


Unclear risk

Reported adverse events in randomised patients. Conference proceeding, no detail information was provided for lost of follow up or drop outs


86

Chew 1994

(Continued)


Low risk

Conference proceeding, no detail information was provided, but reported expected outcomes

Other bias

Low risk

Conference proceeding, appears to be free of other sources of bias

Ching 1998 Methods


Participants

Country: Hong Kong, China. 186 H. pylori positive (determined by RUT) patients with PUD or FD

Interventions

Omeprazole 20mg bid amoxicillin 1g bid and clarithromycin 500mg bid for 7 or 10 days. Omeprazole 20mg od was given for 3 weeks for patients with PUD

Outcomes

H. pylori eradication (assessed by UBT or RUT) 4 weeks after completion of triple therapy, eradication rate for subgroup of PUD and FD. Ulcear healing,

Notes

PUD subgroup was excluded by Fuccio 2007 meta-analysis due to H. pylori assessed one week after omeprazole 20mg od. PUD subgroup was excluded in sensitivity analysis in this review

Risk of bias Bias




”randomised to“ at ”4:1“ ratio. No other information was provided



Unclear risk


Open trial. Participants and personnel were not blinded.




Low risk

No patient drop out. Eradication reported for all randomised patients


Low risk

No patients drop out. Overall side effect incidence and detail of individual adverse event were provided in table 2


87

Ching 1998

(Continued)


Low risk


Other bias

Low risk


Cho 2001 Methods

Multicentre RCT

Participants

Country: South Korea. 255 PUD patients with H. pylori infection (determined by UBT)

Interventions

Omeprazole 20mg bid, amoxicillin 1g bid and clarithromycin 500 mg bid for 7, 10 or 14 days

Outcomes

H. pylori eradication (assessed by UBT) 4 weeks after completion of treatment

Notes

The authors stated that they excluded patients with low compliance (< 80%) in the study. But it is not clear whether these patients were counted in ITT, Therefore this study was excluded in the sensitivity analysis

Risk of bias Bias




”randomly“, no detail information was provided for randomisation method



Unclear risk


No information was provided for whether any party was blinded


No information was provided for whether outcome assessor (for UBT) was blinded


Unclear risk

It seems that no patient lost to follow up, eradication reported in all ”analysed patients“. However, we don’t know whether any patients were excluded in the analysis due to ”low compliance“


Unclear risk

Adverse events were reported in table 3, as total patients and individual events. However, we don’t know whether any patients were excluded in the analysis due to ”low compliance“, and how many of them had adverse events


88

Cho 2001

(Continued)


Low risk


Other bias

Low risk


Cui 2002 Methods

Single-centre, RCT

Participants

Country: China. 147 patients with upper GI symptoms andH. pylori associated gastritis determined by RUT, histology and culture (at least 2 positive), or only UBT positive

Interventions

Pantoprazole 40 mg bid, amoxicillin 1g bid and metronidazole 400 mg bid for 1 or 2 weeks, or omeprazole 20 mg bid, amoxicillin 1g bid and metronidazole 400mg bid for 1 or 2 weeks

Outcomes

H. pylori eradication after 4 weeks (all RUT, histology and culture negative, or UBT negative), GI symptom relief

Notes

Two different criteria were mentioned for H. pylori eradication confirmation in the text in two different places. (one was all RUT, histology and culture negative, one was UBT negative. Maybe because some patients did not go for EGD

Risk of bias Bias




”Randomized to“. no detail information was provided for randomisation method



Unclear risk




No information was provided for whether outcome assessor was blinded


Low risk

It seems that no patient lost to follow up, eradication reported in all randomised patients


Unclear risk

It seems all patiens completed the treatment, however, adverse events were not reported for individual duration group


89

Cui 2002

(Continued)


High risk

Adverse events were reported as total patients for pantoprazole or omeprazole patients. It is not clear how many patients had adverse events in each duration group

Other bias

Low risk


Daghaghzadeh 2007 Methods

Two-centre, RCT

Participants

Country: Iran. 156 patients with DU or GU or chronic active gastritis with dyspepsia resistant to conventional therapies and H. pylori infection (determined by RUT or histology)

Interventions

Omeprazole 20 mg bid, bismuth subcitrate 240 mg bid, furazolidone 200mg bid and amoxicillin 1 g bid for 7 or 14 days. PUD patients received 1 month omeprazole 20 mg od after eradication

Outcomes

H. pylori eradication (assessed by UBT) 4 weeks after the end of treatment, or 2 weeks after the end of omeprazole od for PUD patients

Notes

Omeprazole was used 20mg od for one month after eradication in PUD patients and H. pylori eradication test was performed 2 weeks after.

Risk of bias Bias




”randomised into“, no detail information was provided for randomisation method



Unclear risk






Low risk

It seems no patient lost to follow up, although some patients discontinued treatment due to adverse events. Eradication rate reported in ITT and PP sample


Low risk

It seems no patient was lost of follow up, although some patients discontinued treatment due to adverse events. Aderse events re-


90

Daghaghzadeh 2007

(Continued)

ported as event rate in table 3. Authors replied as for the patients’ number with adverse events in both groups Selective reporting (reporting bias)

Low risk


Other bias

Low risk


Dal Bo’ 1998 Methods


Participants

Country: Italy. 129 dyspeptic patients with gastritis and H. pylori infection (determined by histology and RUT and pathological levels of anti-H. pylori IgG). 99 patients were included in this systematic review.

Interventions

Omeprazole 20mg bid, clarithromycin 250mg bid, metronidazole 250mg qid for 1 week (n=66) or 2 weeks (n=33). The third group: DeNol 120 qid, clarithromycin 250mg bid, metronidazole 250mg qid for 2 weeks (n=30)

Outcomes

H. pylori eradication after 8 weeks assessed by RUT, histology and serum level of antiH. pylori IgG

Notes

Low dose regimen

Risk of bias Bias




“randomly”, no detail information was provided for randomisation method



Unclear risk


Open trial, participants and physicians were not blinded.


“operators who performed the test and lab assessment were not aware of the results of patient’s H. pylori status.


Eradication reported in ITT and PP sample. 25 patients dropped out because they were symptom-free so refused the follow up endoscopy. It is unlikely this drop out has impact on the eradication rate comparison between the groups

Low risk


91

Dal Bo’ 1998

(Continued)


Low risk

Paients with adverse events reported in table 2. 25 patients dropped out because they were symptom-free so refused the follow up endoscopy. It is unlikely this drop out has impact on the adverse event rate comparison between the groups


Low risk


Other bias

Low risk


Dammann 2000 Methods

Multicentre, double-blind, RCT

Participants

Country: Germany. 254 patients were randomised but included 244 patients with active DU and H. pylori infection (determined by RUT positive and at least one of additional test positive from histology, culture or UBT)

Interventions

Pantoprazole 40mg bid, clarithromycin 500mg bid and metronidazole 500mg bid for 7 (n=121) or 14 days (n=123) (metronidazole only used for 10 days in 2 weeks group due to labelling reasons)

Outcomes

H. pylori eradication after 6 weeks (at least 3 out of 4 tests available and all results were negative); ulcer healing rate, GI symptoms, gastritis scores, antibiotic resistance before and after treatment

Notes

254 patients were randomised but only 244 met inclusion criteria after, by excluding10 H. pylori negative patients (this was authors’ ITT, we also considered this as the proper ITT). Authors’ MITT only included patients had test results. ”patients who had to be withdrawn were subsequently replaced“ but it is not clear whether any patients had been replaced. Metronidazole used only 10 days in 2 weeks group. Therefore, this study was excluded in the sensitivity analysis In this study population, for 188 patients had resistance test at baseline, 32% resistant to metronidazole, 2% resistant to clarithromycin. One of these patients showed resistance to both antibiotics. In 13 patients that had resistance testing results at the end, all showed a resistance to metronidazole and 12 showed additionally resistance to clarithromycin. Nine patients developed a resistance to clarithromycin and six patients to metronidazole

Risk of bias Bias




”randomized“, no detail information was provided for randomisation method



Unclear risk


92

Dammann 2000

(Continued)

Blinding of participants and personnel Low risk (performance bias) All outcomes

Double blind study, patients and physicians were blinded.


It is not clear whether outcome assessors for H. pylori eradication were blinded. Based on the study design, it is likely that outcome assessors were blinded as well


Low risk

Eradication was reported in ITT and PP sample. Altough 14 vs 17 test results not available, it unlikely has impact on treatment effect, because they were balanced between the two groups


Unclear risk

Adverse events were reported in ITT sample. 11 patients discontinued due to adverse events, however, it is not known the number of patients in each group


High risk

11 patients discontinued due to adverse events, however, it is not known the number of patients in each group

Other bias

Low risk


de Boer 1994 Methods

Single-centre RCT

Participants

Country: the Netherlands. 111 patients with history of GU or DU and H. pylori infection (determined by RUT and histology)

Interventions

CBS 120mg qid, tetracycline 500mg qid and metronidazole 500mg tid for 1 or 2 weeks. Most patients were on H RAs and they were advised to continue their regular acidcontrolling drugs (usually cimetidine or ranitidine)

Outcomes

H. pylori eradication rate after 4 to 6 weeks by RUT and histology or UBT alone (if refused EGD), adverse event

Notes

Most patients were either on maintenance treatment with H RAs or were taking H RAs on demand, the authors labelled this as “quadruple therapy”, although the dose for H RAs was not known and type of H RAs were not the same or not randomised. We consider it as bismuth triple therapy. The H. pylori diagnostic method before anatomizations was biopsy proven“, we presume it was the same as the post-treatment method under EGD (history and RUT)

Risk of bias Bias




93

de Boer 1994

(Continued)


”randomly assigned“, no detail information was provided for randomisation method



Unclear risk






Low risk

Eradication rate reported in ITT and PP sample. Altough 1 patient in each group lost to follow up, it unlikely has impact on treatment effect


Low risk

Adverse events reported in table 3, as total patients with adverse events or individual event number. Altough 1 patient in each group lost follow up, it unlikely has impact on the adverse event analysis


Low risk


Other bias

Low risk


De Francesco 2004 Methods

Two-centre RCT

Participants

Country: Italy. 347 patients with dyspeptic symptoms for at least one month (PUD or FD) with H. pylori infection (by UBT, RUT and histology, at least two were positive)

Interventions

Rabeprazole 20mg bid, clarithromycin 500mg bid and amoxicillin 1g bid for 7 days (n=115) or 10 days (n=116), or, the 10-day sequential regimen: rabeprazole 20mg bid+amoxicillin 1g bid for 5 days then rabeprazole 20mg bid+ clarithromycin 500mg bid+tinidazole 500mg bid for 5 days (n=116)

Outcomes

H. pylori eradication after 6-8 weeks of therapy (assessed by all UBT, RUT and histology), factors affecting outcome, eradication rate in PUD and FD patients, respectively. adverse events





94

De Francesco 2004

(Continued)


”computer-generated list“



Unclear risk






Low risk

Eradication reported in ITT and PP sample. One patient in both eligible groups lost to follow up, it unlikely has impact on treatment effect


Low risk

Adverse events reported for individual event and in total patient number with adverse event. it unlikely the 2 lost of follow up patients have impact on the adverse event effect


Low risk


Other bias

Low risk


Di Caro 2002a Methods

Single-centre, open study, RCT.

Participants

Country: Italy. 160 patients (PUD or mucosal inflammation or normal mucosal) with H. pylori infection (documented by UTB and histology). 80 patients were included in this systematic review

Interventions

Rabeprazole 20mg od and levofloxacin 500mg od for 5, 7 or 10 days, or rabeprazole 20mg od, levofloxacin 500mg od and amoxicillin 1g bid for 7 days. 40 patients per group

Outcomes

H. pylori eradication after 6 weeks assessed by UBT, adverse events.





Support for judgement ”Subjects were randomly assigned, following a computer generated list“

95

Di Caro 2002a

(Continued)


Low risk

”Randomization allocation was concealed by means of sequentially numbered, sealed envelopes“


Open study. The patients and the physicians were not blinded




Low risk

Eradication reported in ITT sample, all patients completed the therapy


Low risk

Patients with adverse events were reported. No patient withdrew from treatment due to adverse events


Low risk


Other bias

Low risk


Di Mario 2003a Methods

Single-centre, open, RCT.

Participants

Country: Italy. 150 patients (PUD or gastritis, all had dyspeptic symptoms) with H. pylori infection (determined by histology+ UBT or histology+ HpSA positive)

Interventions

Rabeprazole 20mg bid, clarithromycin 500mg bid and tinidazole 500mg bid for 7 days (n=52) or 10 days (n=47), or rabeprazole 20mg bid, clarithromycin 500mg bid, tinidazole 500mg bid and bovine lactoferrin 200mg bid for 7 days (n=51)

Outcomes

H. pylori eradication 8-10 weeks after completion of treatment (assessed by UBT or HpSA), adverse events




Support for judgement ”randomised list“, no detail information was provided for randomisation method


96

Di Mario 2003a

(Continued)


Unclear risk



Open study, patients and physicians were not blinded.




Low risk

Eradication rate reported in ITT and PP sample. Altough 1 patient in 7 days and 3 patients in 10 days discontinued treatment due to adverse events, these patients were considered as treatment failure


Low risk

Adverse events reported in patients completed the treatment, the patients withdrew treatments were due to adverse events


Low risk


Other bias

Low risk


Dore 2011 Methods


Participants

Country: Italy. 417 patients with dyspeptic symptoms who underwent upper endoscopy and diagnosed with H. pylori infection (histology). 3.8% of them were PUD.

Interventions

Pantoprazole 20 mg+ tetracycline 500 mg+ metronidazole 500 mg + bismuth subcitrate caplets 240 mg, bid (with the midday and evening meals), for 14 days (n=202) or 10 days (n=215)

Outcomes

H. pylori eradication 40-50 days after completion of eradication therapy assessed by history or UBT; adverse events, compliance, cost analysis

Notes

Information for adverse events was unclear, contacted author and got replies

Risk of bias Bias




97

Dore 2011

(Continued)


“Randomization was concealed and done by use of sealed envelopes containing one of the treatment protocols prepared from a list of random numbers generated by a computer.”


“sealed envelopes” were used. “An independent medical staff member assigned subjects to the two schedules. After the regimen was identified, the treatment was open label”

Low risk


Open-label study. Physicians and patients were not blinded.


All breath tests were analysed at the same laboratory. The outcome assessors in the lab were likely blinded. Adherence and side effects assessed by a physician unaware of the eradication regimen both by direct questioning and by the number of days the patient took the study medication


Low risk

Eradication rate reported in ITT and PP sample. PP analysis excluded 9 patients lost to follow up (7 in 14 days group and 2 in 10 days group) and 7 patients discontinued therapy due to adverse events (3 in 14 days vs 4 in 10 days). More patients lost to follow up in 14 days group maybe attribute to the adverse events, we used ITT sample in the eradication analysis


Low risk

Figure 1 and table 4, 5, gave details for withdrew, lost to follow up, and side effects


Low risk

Reported all expected outcomes.

Other bias

High risk

Authors responded adverse events as 32 vs 22 in total. However, the unfitness/ discomfort only was 40 vs 18, fatigue/ weakness as 32 vs 20 in table 5. Authors replied our enquiry that those were patients’ filling events so were not considered as side effects. It is unclear how the primary authors considered which patients who reported adverse events did have adverse events

Emami 2006 Methods

Single-centre, double-blind, RCT

Participants

Country: Iran. 139 patients with PUD or FD and H. pylori infection (determined by RUT or histology). Two groups with 46 patients were included in this review


98

Emami 2006

(Continued)

Interventions

6 groups, two of the eligible groups were: omeprazole 20mg bid, bismuth 240mg bid, tetracycline 750mg bid and metronidazole 500mg bid for 7 or 14 days (23 patient each group), other 4 groups were quadruple therapy for 3 or 7 days with sugar or levodopa. All patients had omeprazole 20mg bid for 2 days pre-treatment, famotidine 40mg hs x4 weeks post-treatment

Outcomes

H. pylori eradication after 8 weeks assessed by RUT and histology, ulcer symptom, EGD findings

Notes

Author’s ITT did not include all the randomised patients (excluded 18 patients refusal to EGD, 11 patients with side effects and 1 patient non-compliance). We used randomised sample as ITT in the analysis. Post-treatment assessment after 8 weeks = at least 6 weeks antibiotics-free but only 2 weeks famotidine-free period, therefore this study was excluded in sensitivity analysis

Risk of bias Bias




“randomized into”, no detail information was provided for randomisation method


Patients were referred to the clinical pharmacist responsible for prescriptions and completion of the questionnaires on medication side effects and compliance“ It is not clear whether the pharmacists were responsible to the randomisation list as well

Unclear risk


”double blind“ study. We presume patients and physicians were blinded


It is unclear whether outcome assessors were blinded (for RUT and histology). It is likely they were blinded in a real double blind study


The authors’ ITT was not the randomised sample (excluded 18 patients refusal to EGD, 11 patients with side effects and 1 patient non-compliance in all 6 groups). We used randomised sample as ITT in the analysis, and presume all excluded patients failed treatment (5 in 7 days group and 6 in 14 days group). It is unclear whether the excluded patients have impact on the eradication effect between the two groups

Unclear risk


99

Emami 2006

(Continued)


Unclear risk

Authors excluded 18 patients refusal to EGD, 11 patients with side effects and 1 patient non-compliance from 6 groups. It is not clear how many of the 11 patients with adverse events belong to each group, because medication side effects was one of the exclusion criteria. Thus, we can not include this study in the analysis of adverse events


Low risk

H. pylori eradication was the only outcome in this study.

Other bias

Low risk


Ercin 2010 Methods

SIngle-centre, RCT

Participants

Country: Turkey. 91 FD patients with H. pylori infection, diagnosed by histology and RUT test.

Interventions

Lansoprazole 30 mg bid, levofloxacin 500mg od and amoxicillin 1g bid, for 7 or 14 days

Outcomes

H. pylori eradication 4 weeks after completion of eradication assessed by UBT, adverse events

Notes

Authors reported eradication rate in PP sample. High (15%, 14/91) lost follow-up and low eradication rate in this study (34% vs 72% in PP sample), we counted lost follow-up as treatment failure in the ITT sample. Authors considered high levofloxacin resistance in Turkey

Risk of bias Bias



Random sequence generation (selection High risk bias)

“randomly separated”, did not provide further details. Sample size was imbalanced between the two groups (51 vs 40), it is questionable whether it was a true randomisation trial


Unclear risk







100

Ercin 2010

(Continued)


High risk

Reported eradication in PP sample only, we calculated eradication rate in ITT sample. High lost follow-up rate (15%) because of the lost of contact. It is impossible to know the outcome of these patients so we presumed them all had failed eradication. The lost of contact was imbalanced between the two groups (9/ 51 vs 3/40), with 20% in 7 days group and 10% in 14 days group


High risk

Only reported adverse events that caused stopped treatment: only 2 patients stopped treatment due to adverse events, Contacted the author, replied: ”all completed study except the 9+3 patients lost follow up, all other patients had no adverse events“. Compliance was recorded, authors replied that except the lost follow up and adverse events, all patients completed the treatment days and took all the drugs. However, the lost of contact was imbalanced between the two groups (9/51 vs 3/40)


Low risk


Other bias

Low risk


Fennerty 1998 Methods

Multi-centre, double-blind, RCT

Participants

Country: USA. 284 patients (active or history of DU but with chronic gastritis) with positive H. pylori (randomised based on positive RUT first, then confirmed by positive histology or culture)

Interventions

Lansoprazole 30mg bid, amoxicillin 1g bid, and clarithromycin 500mg bid for 10 (n= 148) or 14 days (n=136)

Outcomes

H. pylori eradication 4 to 6 weeks after assessed by histology and culture, ulcer status, resolution of gastritis, antimicrobial susceptibility before and after treatment, resolution of symptoms, adverse events

Notes

284 patients were randomised based on positive RUT then then excluded patients if not confirmed by histology and/or culture (confirmed H. pylori infection in 258, 90%) ; however, authors’ ITT included only 261 (92%=135 vs 126), therefore we used randomised ITT in the analysis, and used authors’ ITT in the sensitivity analysis In addition, authors used the randomised sample to report the adverse events (patients excluded for H. pylori analysis were considered as no adverse events), which might underestimated the adverse events 87% had active DU, all others had DU history within one year, this study was put under the subgroup of PUD in subgroup analysis In this study population, 17/124 (13.7%) isolates were primary resistant to clarithromycin, the purported resistance to amoxicillin could not be confirmed for 2/124.


101

Fennerty 1998

(Continued)

Developed resistance was 2/107 to clarithromycin and 0/122 to amoxicillin Risk of bias Bias




“randomized to”. No detail provided for randomisation method



Unclear risk


Double blind study. All study medication was matched with placebo to maintain the double-blind nature of the study


Pathologist was blinded to the patients’ clinical status and treatment and to the results of the other rests


Unclear risk

Patients first were included and randomised if RUT was positive, then 23 patients were excluded if not confirmed by histology and/or culture (13 from 10 days and 10 from 14 days group), We used the randomised ITT in the analysis and used authors’ ITT in the sensitivity analysis. Within the 12 patients had low compliance, it is unclear why 7 of them excluded from the PP analysis and 5 of them were considered as treatment failure


Unclear risk

Adverse events were reported. Authors used the randomised sample to report the adverse events (patients excluded for H. pylori analysis were considered as no adverse events), which might underestimated the adverse events, although only 23 patients (13 vs 10) were excluded and was balanced between groups


Low risk


Other bias

Low risk



102

Filipec Kanizaj 2009 Methods

Single-centre, RCT

Participants

Country: Croatia. 592 naive H. pylori-positive patients with dyspeptic complaints, all underwent an upper GI endoscopy in the referral centre for H. pylori investigation (GU, DU or FD). H. pylori infection was proven by: histology (96% patients positive), microbiology (79% positive), and/or rapid urease (98% positive) examination. Patients were considered H. pylori positive if more than one of applied methods was positive.

Interventions

Patients were randomised to pantoprazole (40 mg bid), amoxicillin (1000 mg bid), metronidazole (500 mg bid) or clarithromycin (500 mg bid) for 14 (n=58 and n=57), 10 (n=117 and n=118), or 7 days (n=122 and n=120), respectively, followed by 14 days of pantoprazole (40 mg once daily) maintenance treatment

Outcomes

H. pylori eradication rate (histologic, microbiologic and RUT, all negative) assess 4-6 weeks after treatment, in all patients, in patients with non-resistant and resistant H. pylori strains; clinical factors related to H. pylori eradication success; adverse events.

Notes

In table 5, adverse events reported in ITT sample for PAC, but not clear for PAM (the number used was PP sample size for PAC), seems a mistake for the sample size in the table In 467 patients that have data, primary resistance to clarithromycin and metronidazole was 8.2% and 32.9%, respectively

Risk of bias Bias




”a random number generator“ was used.


”Prior to the study, sealed envelopes containing different treatment protocols have been produced, numbered, and ordered using a random number generator. Personnel not involved in the trial assigned the subsequent envelopes to patient according to order of their referral to examination“

Low risk




Outcome assessed by personnel who did not know which protocol was used


No incomplete data. Randomized sample and lost to follow up provided in figure 1. Eradication data reported in ITT and PP sample

Low risk


103

Filipec Kanizaj 2009

(Continued)


Unclear risk

Adverse events reported in table 5, adverse events reported in ITT sample for PAC, but not clear for PAM (the number used was PP sample size for PAC), seems a mistake for the sample size in the table. We noticed a mistake about ”patients number did not take more than 90% of the prescribed medication“ in the report, contacted authors, obtained correct number as 18 instead of 22


Low risk


Other bias

Low risk


Garza González 2007 Methods

Single-centre RCT

Participants

Country: Mexico. 59 H. pylori positive patients with dyspeptic symptom determined by RUT, histology and culture (2 or more tests positive)

Interventions

Rabeprazole 20mg od, amoxicillin 1g bid, clarithromycin 500 mg bid, for 7 days or 14 days

Outcomes

H. pylori eradication 4 weeks after completion of therapy assessed by HpSA. Effect of CYP2C19 status and bacterial resistance on eradication rate

Notes

ITT by authors included patients took at least one dose. Before the study, population CYP2C19 was determined for the purpose of sample size. In the eligible subjects, 72.9% of subjects were Hom-EMs, 15.3% were Het-EMs, and 11.9% were PMs. Genotyperelated eradication rate only provided for PP sample. 14 days group had fewer PMs (2 vs 4) and more resistant stains to clarithromycin ( 4% vs 11.1%). In total, 7.7% of 52 patients had stains resistant to clarithromycin, none of them resistant to amoxicillin The study did not report adverse event.

Risk of bias Bias




No detail information was provided for randomisation method.



Unclear risk




104

Garza González 2007

(Continued)


It is unclear whether outcome assessors (for stool antigen) were blinded


Low risk

Eradication rate was reported in ITT and PP sample. PP sample included only patients that completed the regimen including the eradication test


Unclear risk

This study did not report adverse events. PP sample included only patients that completed the regimen including the eradication test. It is not clear how many of them stopped treatment due to adverse events


Low risk


Other bias

Low risk


Gisbert 2005a Methods

Multicentre; open, RCT

Participants

Country: Spain. 450 DU patients with H. pylori infection (determined by UBT or RUT or histology). 300 patients were included in this systematic review

Interventions

Esomeprazole 40mg bid, clarithromycin 500mg bid and amoxicillin 1g bid for 7 or 10 days, or esomeprazole 20mg bid, clarithromycin 500mg bid and amoxicillin 1g bid for 7 days, 150 patients per group

Outcomes

H. pylori eradication 8 weeks after completion of therapy assessed by UBT. Adverse events

Notes

Esomeprazole 40mg bid is considered as high dose in this review

Risk of bias Bias




“Randomization was carried out using a table of contingent numbers, by blocks”


“Concealment of allocation of the sequence of randomization was not performed.”

High risk


Open trial, patients and physicians were not blinded.


105

Gisbert 2005a

(Continued)


“Breath test was carried out by operators unaware of therapy and patients’ H. pylori status”


Low risk

Eradication reported in ITT and PP sample. 12 vs 14 patients lost to follow up or protocol violations; it is unlikely it has impact on the treatment effect estimate


Unclear risk

Patient numbers reported adverse events were reported. However, it is not clear how many lost of follow-up patients had adverse events in each group


Low risk


Other bias

Low risk


Grade 1996 Methods

Single-centre RCT

Participants

Country: USA. 20 patients with FD and H. pylori infection (by RUT and histology)

Interventions

Omeprazole 20mg bid, amoxicillin 1g bid and clarithromycin 500mg bid for 7 or 10 days

Outcomes

H. pylori eradication after 4 weeks by UBT; symptom score, gastritis score

Notes

Contacted author and the excluded allergy patient might be in the 7 days group

Risk of bias Bias




”patients were randomized to..“no detail information was provided, conference proceeding


Unclear risk

No information was provided, conference proceeding.




No information was provided,conference proceeding.


106

Grade 1996

(Continued)


Low risk

”one patient was withdrawn because of an allergic reaction“. This patient was excluded by the primary author from their analysis. We contacted the author, replied us since he was unable to locate the files, his ”best guess is that that patient belonged to the 7day course“. We calculated the eradication rate based on ITT sample according to this information. It is unlikely this patient have impact on the effect estimate


Unclear risk

One patient was excluded in the analysis due to allergy. We contacted author therefore were able to have the ITT data. No detail information provided for adverse events in this conference proceeding


Low risk


Other bias

Unclear risk

Conference proceeding. Insufficient information to assess whether an important risk of bias exists

Gumurdulu 2004 Methods

Single-centre RCT

Participants

Country: Turkey. 164 patients with PUD and H. pylori infection (determined by histology), of them, 112 patients were included in this review

Interventions

Omeprazole 20mg bid, clarithromycin 500mg bid amoxicillin 1g bid for 1 (n=53) or 2 weeks (n=59), or bismuth subcitrate 300mg qid, tetracycline 500mg qid, metronidazole 500mg qid and omeprazole 20mg bid for 10 days (n=52)

Outcomes

H. pylori eradication 45-60 days after treatment assessed by histology; ulcer healing, factors related to eradication rate

Notes

Seems have a typo as “antibiotics, PPIs and H2RAs were used for at lease one month” for PUD patients should be “ makes no sense in light of the design of the study, three drugs can’t used for more than one month for PUD patients. Excluded in sensitivity analysis. In addition, the authors stated they included 164 patients in the study, but also mentioned ”out of 164 patients who completed the study..“, it is not clear whether any patients were excluded in the paper because they did not completed the study. We contacted the authors but no response. The very low eradication rates in this study are also outside the normal range

Risk of bias Bias




107

Gumurdulu 2004

(Continued)


“randomly divided into three groups”, no detail information was provided for the randomisation method



Unclear risk


No information was provided whether patients and physicians were blinded


No information was provided whether outcome assessors were blinded (histology)


Unclear risk

The authors stated they included 164 patients in the study, however, they also mentioned ”out of 164 patients who completed the study..“ in the text, it is not clear whether any patients were excluded in the paper because they did not completed the study. We contacted the authors but no response, we presumed the PP sample and ITT sample was the same as 164. No data was provided for withdrawal and dropout


Unclear risk

This study did not reported adverse events. No data was provided for lost to follow up or dropout


Low risk

Authors reported factors related to eradication rate and ulcer healing rate as planned

Other bias

Low risk


Hsu 2005 Methods

Single-centre, open, RCT.

Participants

Country: Taiwan. 120 patients with PUD or FD and H. pylori infection (by RUT and histology or culture) (RUT for randomisation, the other two for PP analysis)

Interventions

Famotidine 40mg bid, amoxicillin 1g bid and tinidazole 500mg bid for 7 or 14 days. Antacids were allowed

Outcomes

H. pylori eradication 4 to 6 weeks after treatment (by RUT, histology and culture); H. pylori eradication and ulcer healing, primary and acquired resistance, impact of primary resistance to metronidazole on eradication rates; adverse events

Notes

Primary metronidazole resistance rate was 33.1% in this study, however, the resistance rate was significant higher in 14 days group vs 7 days groups (41.4% vs 25%). In 21 patients who failed eradication, all of them found to be resistant to metronidazole both before and after therapy


108

Hsu 2005

(Continued)

Risk of bias Bias




“randomly assigned”, no information provided for randomisation method



Unclear risk




“Pathologist and microbiologists were blind to the drugs treatment given to the patients”


Low risk

Eradication reported in ITT and PP sample. 6 vs 5 patients lost of follow up, 0 vs 2 missing data, it unlikely has impact on the eradication effect between the two groups


Low risk

Adverse events reports in table 3, for total patients with adverse events and individual adverse events. 6 vs 5 lost of follow up, 0 vs 2 missing data, The numbers were balanced between the two groups


Low risk


Other bias

Low risk


Hu 1999 Methods

Single-centre RCT

Participants

Country: China. 46 patients with active DU and H. pylori infection determined by RUT, histology and culture (at least 2 positive)

Interventions

Lansoprazole 30mg bid for 2 weeks, amoxicillin 1g bid and metronidazole 400mg bid for 1 (n=21) or 2 weeks (n=25). Lansoprazole used for two weeks in both groups

Outcomes

H. pylori eradication 4 weeks after completion of therapy assessed by RUT and histology and culture, ulcer healing, pain relief, adverse events

Notes Risk of bias Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

109

Hu 1999

(Continued)

Bias




“randomized to”, no detail information was given for randomisation method. The sample size was imbalanced between the two groups


Unclear risk







Unclear risk

It seems all included patients completed the study. However, it is not clear whether the reported sample was the ITT sample or the PP sample, the term ”ITT“ was not mentioned, and the sample size was imbalanced between the two groups


Unclear risk

It seems all included patients completed the study, adverse events were reported. However, it is not clear whether the reported sample was the ITT sample or the PP sample


Low risk


Other bias

Low risk


Hu 2003 Methods

Multicentre RCT

Participants

Country: China, 128 patients with gastritis or DU and H. pylori infection determined by UBT, histology and culture (at least 2 positive)

Interventions

Famotidine 20 mg bid, amoxicillin 1g bid and metronidazole 400 mg bid for 7 days (n= 25) or 14 days (n=38); omeprazole 20 mg bid, amoxicillin 1g bid and metronidazole 400 mg bid for 7 days (n=26) or 14 days (n=39)

Outcomes

H. pylori eradication 4 weeks after completion of therapy assessed by UBT, histology and culture; pain relief, adverse events

Notes

After patients were randomised to H RA based or PPI based therapy, it is not know whether patients were randomised to 1 week or 2 weeks therapy. The sample size was not balanced between 7 days vs 14 days within the same regimen, however, it was balanced between two 7 days and two 14 days. This study was excluded in the sensitivity analysis


110

Hu 2003

(Continued)

Risk of bias Bias




“randomized to”, no detail information was given for randomisation method. Although patients were randomised to H RA based or PPI based therapy, it is not know whether patients were randomised to 1 week or 2 weeks therapy. The sample size was not balanced between 7 days vs 14 days within the same regimen, however, it was balanced between two 7 days and two 14 days


Unclear risk







Unclear risk

It is unclear whether the reported patients here were the randomised patients or PP sample. The term ”ITT“ was not mentioned


Unclear risk

It is unclear whether the reported patients here were the randomised patients or PP sample. The term ”ITT“ was not mentioned. Adverse events were reported in mixed group, therefore no data was available for adverse events


High risk

Adverse event reported in mixed H RA based groups and the mixed PPI based groups

Other bias

Low risk


Hu 2004 Methods

Multicentre RCT

Participants

Country: China. 258 patients with active DU and H. pylori infection (determined by RUT and histology)

Interventions

(1) omeprazole 20 mg bid amoxicillin 1 g bid and clarithromycin 250 mg bid for 1 week (n=47) or 2 weeks (n=42), (2) omeprazole 20 mg bid, amoxicillin 1g bid and clarithromycin 500 mg bid for 1 week (n=40) or 2 weeks (n=41), (3) omeprazole 20 mg bid, amoxicillin 1g bid and metronidazole 400 mg bid for 1 week (n=44) or 2 weeks (n= 44)


111

Hu 2004

(Continued)

Outcomes

H. pylori eradication after 4 weeks assessed by RUT and histology; ulcer healing and recurrence, adverse events

Notes

Omeprazole was mistakenly as 0.2mg in the text.

Risk of bias Bias




“randomized to”, no detail information was given for randomisation method


Unclear risk







Low risk

Eradication reported in ITT and PP sample. In total, 10 patients lost to follow up or dropped out, it is unlikely to have impact on treatment effect analysis


Unclear risk

Adverse events reported in PP sample, 10 patients lost of follow up or dropped outs. All patients completed treatment, except it is not know whether any of the 10 patient were dropped out due to adverse events


Low risk


Other bias

Low risk


Hurenkamp 2000 Methods

Multicentre; double-blind, RCT.

Participants

Country: The Netherlands. 76 ulcer (acute or previous documented GU or DU) patients with H. pylori infection (determined by histology or culture).

Interventions

Omeprazole 20 mg bid, metronidazole 400 mg bid and clarithromycin 250 mg bid for 4, 7 days (n=25) or 10 days (n=24). Omeprazole 20 mg bid used for 10 days in all groups


112

Hurenkamp 2000

(Continued)

Outcomes

H. pylori eradication after 4 to 6 weeks by history and culture or UBT (if refused EGD) , impact of primary resistance to antibiotics on eradication rate; adverse events

Notes

Not all patients had active ulcer, this study was put in the subgroup of PUD. Of the H. pylori isolates of 75 patients, 16 (21%) and one (1%) were resistant to metronidazole and clarithromycin, respectively. In the two eligible groups, 20% and 0% were resistant to metronidazole and clarithromycin, respectively. Authors suggested ”no influence of metronidazole-resistance or clarithromycin- resistance was observed“

Risk of bias Bias




“randomization” no detail information was provided for the randomisation method



Unclear risk


Double-blind study, patients and physicians were blinded.


The histopathologist and microbiologist were blinded to each other’s results


Low risk

Eradication reported in ITT and PP sample. 2 vs 1 patients had no follow up results but all completed treatment, it is unlikely to have impact on the treatment effect analysis


Low risk

No patients had serious adverse events or stopped treatment due to adverse events. “Two patients complained of stomatitis and glossitis but were able to continue the therapy” however, it is not clear which group they belonged. We considered the proportion of missing outcomes was not enough to have a clinically relevant impact on the effect estimate


Unclear risk

Adverse events were not reported by groups. “Two patients complained of stomatitis and glossitis but were able to continue the therapy” however, it is not clear which group they belonged. We considered the proportion of missing outcomes was not enough to have a clinically relevant impact on the effect estimate

Other bias

Low risk



113

Kang 2000a Methods

Single-centre RCT

Participants

Country: South Korea. 387 H. pylori positive patients (determined by UBT) with PUD

Interventions

Omeprazole 20 mg bid, amoxicillin 1 g bid, and clarithromycin 500 mg bid, 7 days (n= 133) or 10 days (n=116) or 14 days

Outcomes

H. pylori eradication assessed by 13C-UBT 4 weeks after completion of therapy, D13CO2 as predictor for treatment failure

Notes

”poor compliance were excluded in the study“ but not sure whether counted in ITT, contacted authors no reply, therefore this study was excluded in the sensitivity analysis

Risk of bias Bias




”randomly“, conference proceeding, no detail information was provided for the randomisation method


Unclear risk







Unclear risk

”poor compliance were excluded in the study“ but not sure whether these patients were counted in the analysed patients, contacted primary authors no reply


Unclear risk

Adverse events were not reported in this conference proceeding


Unclear risk

Conference proceeding. Reported eradication, did not report adverse event data and it is not sure whether adverse event was one of the planned outcome

Other bias

Unclear risk



114

Karatapanis 2011 Methods

Single-centre, open RCT

Participants

Country: Greece. 307 patients with PUD (57%) or FD (43%) and H. pylori infection (determined by RUT or histology). Pre-treatment culture for clarithromycin sensitivity test was possible in 209 patients

Interventions

Rabeprazole 20mg bid, amoxicillin 1g bid, clarithromycin 500mg bid for 7 or 10 or 14 days

Outcomes

H. pylori eradication 4-6 weeks after completion of treatment assessed by RUT and histology. Eradication reported in clarithromycin resistant H. pylori stains and sensitive stains.Compliance, and adverse events.

Notes

Primary clarithromycin resistance rate was 9.56% in this study population

Risk of bias Bias




“randomized to”, no detail was provided.



Unclear risk


Open-label study, physicians and patients were not blinded.


“the personnel performing the post-treatment evaluation were not aware of the treatment received by the patient


Low risk

Figure 1 the flow diagram provided ITT and PP number, H. pylori eradication was reported in ITT and PP sample.


Low risk

In total, 5 patients lost follow up, and 4 patients discontinued therapy due to adverse events or poor compliance. It was balanced between the three groups. It is unlikely to have impact on the adverse event comparisons between the three groups


Low risk


Other bias

Low risk



115

Katicic 1997 Methods

Single-centre RCT

Participants

Country: Croatia. 345 patients with GU, DU or FD andpositive H. pylori (by RUT, histology and serology)

Interventions

Omeprazole 20 mg bid, amoxicillin 1 g bid for 14 days, metronidazole 500 mg bid for 10 days; omeprazole 20 mg bid, amoxicillin 1 g bid, metronidazole 500 mg bid for 10 or 7 days, omeprazole 20 mg bid, amoxicillin 1g bid, clarithromycin 500 mg for 14, 10 or 7 days

Outcomes

H. pylori eradication after 4 weeks (by RUT, histology and serology), ulcer healing, clinical improvement of ulcers and FD

Notes

Metronidazole used for 10 days only in the OAM 14 days group, therefore this group was excluded in the sensitivity analysis

Risk of bias Bias




“randomly assigned”, conference proceeding, no detail information was provided for the randomisation method


Unclear risk







Unclear risk

Provided eradication data in 329 patients that completed the study, we calculated the ITT eradication rate based on the randomised sample, presumed all did not completed treatment failed to eradication. No information provided for patients that did not complete the study


Unclear risk

This conference proceeding did not report data for adverse events. 329 out of 345 patients completed the treatment; it is not known how many patients discontinued treatment due to adverse events


Unclear risk

Conference proceeding. Did not report adverse event and it is not clear whether adverse event was a planned outcome


116

Katicic 1997

(Continued)

Other bias

Unclear risk


Kaviani 2001 Methods

Two-centre, double-blinded, RCT

Participants

Country: Iran. 240 patients with DU or pre-pylori ulcer and H. pylori infection (determined by RUT or UBT)

Interventions

Ranitiidne 300mg bid+ amoxicillin 1g bid + metronidazole 500mg bid + bismuth subcitrate 240mg bid for 1 or 2 weeks, or, amoxicillin, metronidazole and bismuth subcitrate triple therapy without ranitidine for 2 weeks (n=80 per group). Antacids were allowed

Outcomes

H. pylori eradication 6 weeks after starting the treatment, by RUT and histology and/or UBT (if no EGD), healing of ulcer; pain after treatment, antacid use, adverse events

Notes

H. pylori eradication rate was low in both arms, 62.5% in 14 days vs 23.8% in 7 days

Risk of bias Bias




“Randomization was performed by using a table of random numbers sealed in pockets”


Low risk

“using a table of random numbers sealed in pockets (all prepared by a member of the digestive research centre)”


“Patients and investigators had no knowledge of the type of regimen before prescription”


“Endoscopists and pathologists also had no knowledge of the type of medications used by patients”


Low risk

Eradication rate reported in ITT sample and PP sample. 82.5% of randomised patients were included in the ITT sample, lost to follow up were balanced between the groups, it is unlikely to have impact on the efficacy analysis


Unclear risk

Adverse events were listed in table 4 as the event numbers, however, no total patients’ numbers with adverse events in each group were provided. Although the lost of follow up was balanced between


117

Kaviani 2001

(Continued)

the two groups, it is not clear whether the lost of follow up were related to the adverse events Selective reporting (reporting bias)

Low risk


Other bias

Low risk


Keum 2005 Methods

Multicentre, open, quasi-randomisation trial (by date)

Participants

Country: South Korea. by 352 patients with PUD or erosive gastritis and H. pylori infection (determined by UBT)

Interventions

Amoxicillin 1 g bid, clarithromycin 500 mg bid and a PPI: omeprazole 20 mg bid (n= 94) or lansoprazole 30 mg bid (n=83), esomeprazole 20 mg bid (n=98) or rabeprazole 10 mg bid (n=77) for 1 or 2 weeks

Outcomes

H. pylori eradication rate after 4 weeks assessed by UBT; factors related to eradication rate, adverse events

Notes

Rabeprazole 10mg twice daily is considered to be at low dose, other PPIs twice daily at standard doses. Quasi-randomisation by date

Risk of bias Bias




Patients were assigned to the type of PPI “by lot”, then assigned to one or two weeks by date. It was a quasi-randomisation study and the sample size was imbalanced between 7 days and 14 days group within the same PPI regimen


High risk

Physicians can predict the next patient would be assigned to which group because the randomisation was based on date




Open study. However, it is unclear whether the outcome assessors (eg. lab technicians) for H. pylori eradication were aware of


118

Keum 2005

(Continued)

the treatment patients received. The assessment for H. pylori eradication is unlikely to have been impacted by the open-label design Incomplete outcome data (attrition bias) Eradication

Unclear risk

Eradication rate was provided in ITT sample. However, it is not clear whether any patients discontinued therapy or dropped out, and whether the dropouts have impact on the treatment effect estimate


Unclear risk

Adverse events were reported within the same PPI regimens but not separated for 1 week or 2 week arms, it is not clear whether any patients discontinued therapy or dropped out because of adverse events


High risk

Adverse events were reported within the same PPI regimens but not separated for 1 week or 2 week arms

Other bias

Low risk


Kim 2007 Methods


Participants

Country: South Korea. 598 patients with PUD and H. pylori infection (determined by UBT or RUT or histology)

Interventions

Omeprazole 20 mg bid or other PPIs (esomeprazole 40 mg or rabeprazole 10 mg or pantoprazole 40 mg bid), amoxicillin 1g bid, and clarithromycin 500 mg bid for 7 (n= 337) or 14 days (n=261). Patients received ”additional PPI“ for ulcer healing but no details for duration

Outcomes

H. pylori eradication 5 weeks after completion of acid-suppressing therapy (assessed by UBT); adverse events

Notes

Although the authors claimed that PPIs were at ”equivalent doses“, rabeprazole used in low dose (20mg/day) but no raw data separated for each PPIs. This study was included in the standard dose subgroup. Questionable randomisation, imbalanced sample size, not in ratio

Risk of bias Bias




119

Kim 2007

(Continued)


“randomly assigned”, no detail information was provided for the randomisation method. The sample size was imbalanced between two groups



Unclear risk


“open labelled design”, patients and physicians were not blinded


Open-label study. However, it is unclear whether the outcome assessors (eg. lab technicians) for H. pylori eradication were aware of the treatment patients received. The assessment for H. pylori eradication is unlikely to have been impacted by the open-label design


Low risk

Eradication provided in ITT and PP sample. PP sample excluded patients lost to follow up and patients violated the study protocol, it was balanced between the two groups (6. 8% v 6.8%), it is unlikely to have impact on the efficacy effect analysis


Low risk

Adverse events reported as percentage in table 3, it seems was based on ITT sample. It is unclear how many of the lost of follow up patients (23 vs 18) discontinued treatment due to adverse events. The lost of follow up was balanced between groups (6.8% v 6.8%)


Unclear risk

Compliance was assessed but the data was not reported. It is unclear whether it has impact on our interest outcomes (efficacy and adverse events)

Other bias

Low risk

No other risk of bias was found.The study appears to be free of other sources of bias

Kim 2008 Methods

Multi-centre, double-blind, RCT

Participants

Country: South Korea. 463 patients with H. pylori-positive PUD including ulcer scar by endoscopy examination. H. pylori infection determined by at least two tests (UBT and either of modified Giemsa staining or RUT) had positive results

Interventions

Lafutidine 20 mg bid, clarithromycin 500 mg bid and amoxicillin 1000 mg bid for 7 days or 14 days; lansoprazole 30 mg bid,clarithromycin 500 mg bid, and amoxicillin 1000 mg bid for 7 days; or 14 days. To blind the patient and testing physician, the patient took famotidine 20 mg bid for 7 days after the 7-day eradication therapy in the two 7 days groups. If an active ulcer was found at the baseline endoscopy, it was treated


120

Kim 2008

(Continued)

with famotidine 20 mg bid for 2 (if DU) or 4 weeks (if benign GU), respectively; after the 14 days of eradication therapy or 7 days eradication and 7 days famotidine treatment Outcomes

H. pylori eradication defined as a negative13 C-UBT, 6 weeks after the 14 days of eradication therapy or 7 days eradication and 7 days famotidine treatment (gastroscopy was performed in cases with an active or healing stage ulcer). Other outcomes were ulcer healing rate and symptoms response rate

Notes

Some information was not clear and we found out some mistakes in the paper. We contacted the authors and received extra information such as the adverse event number in the two 14 days groups

Risk of bias Bias




Patients were “consecutively assigned to four regimens using a randomisation scheme”. Author replied used “randomization table” performed by the independent institute


Low risk

No information in the original text. Contacted the authors, responded ”Used randomization table which was performed by the independent institute“ ”So nobody knows whether the patient was allocated into each group until analysis“


“Double blinded” study, patients and physicians were blinded. To blind the patients and the testing physicians, patients in 7 days group also took famotidine 20mg bid. The author also replied that “the patients took fake drugs if they fulfilled the genuine drug medication period so that the patients or doctors could not differentiate each group.”


No information was given, but since the physicians were blinded, it is likely the outcome assessor who performed the UBT was blinded


Low risk

Figure 1 provided flow chart for ITT and PP sample. Detail was provided for compliance, lost to follow up, discontinued therapy due to adverse events, and protocol violation. Eradication rate was reported in ITT sample


Low risk

Adverse events were reported in table 3 in ITT sample. Contacted the authors and corrected the mistake


121

Kim 2008

(Continued)


Low risk


Other bias

Low risk


Kiyota 1999 Methods

Two-centre, open, RCT

Participants

Country: Japan. 147 patients with PUD and H. pylori infection (determined by culture or histology)

Interventions

Omeprazole 20 mg bid + amoxicillin 1 g bid + clarithromycin 400 mg bid for 1 (n=78) or 2 weeks (n=69). Omeprazole 20 mg od for 2 weeks then ranitidine 300 mg od for 4 weeks

Outcomes

H. pylori eradication after completion of 4 weeks ranitidine assessed by UBT, histology and culture; adverse events

Notes

Post-treatments test was ”after completion of the 4-week ranitidine period“. Therefore this study was excluded by the meta-analysis by Fuccio 2007. Authors’ ITT included all patients who had taken at least one dose of study medication, it is unclear whether any randomised patients were excluded because did not take any medication; the sample size was imbalanced between the two groups. This study was excluded in the sensitivity analysis

Risk of bias Bias




“randomly treated”, contacted authors, replied “by table of random numbers”, However, the sample size was imbalanced between the two groups



Unclear risk


In the text, it was “single blind” study, we contacted the authors inquired for which part was blinded, the authors responded that it was a open RCT, which means patients and physicians were not blinded at all. It is unclear which party in the study was blinded




122

Kiyota 1999

(Continued)


Low risk

Eradication reported in ITT and PP sample, although patients did not come for the second endoscopy were excluded from the PP analysis, the dropouts were balanced between the two groups, it is unlikely to have impact on the treatment efficacy analysis


Low risk

Adverse events reported in table 3, total patients had adverse events and the individual adverse events were reported


Low risk


Other bias

Low risk


Knigge 1999 Methods

Two-centre RCT

Participants

Country: USA. 105 patients with H. pylori infection (determined by UBT)

Interventions

Ranitidine bismuth citrate 400mg bid, metronidazole 500mg bid and tetracycline 500mg bid for 7 (n=54) or 10 days (n=51)

Outcomes

H. pylori eradication after 4 weeks or more assessed by UBT; adverse events





Randomized by “means of opaque randomized envelopes”, although no further details, we presume the randomisation method was adequate


Randomized by “means of opaque randomized envelopes”, it is not stated whether the envelope number was sequential. We considered it as low risk

Low risk


No information was provided whether patients and physicians were blinded


No information was provided; it is not clear whether outcome assessors (for UBT) were blinded


123

Knigge 1999

(Continued)


Unclear risk

Eradication rate reported in ITT and PP sample. However, it is unclear why fewer patients were included in the PP analysis in the 10 days group vs 7 days group (86.3% of ITT vs 96.3% of ITT); except the compliance rate was lower in 10 days group


Unclear risk

Adverse events reported as percentage, it is unclear the authors used ITT or PP sample size to calculate the adverse event rate. We used ITT number to do the calculation. Individual adverse event were reported but combined the data for the two groups. It is unclear the two patients discontinued due to adverse events were belonged to which group


High risk

Individual adverse event was reported but combined the data for the two groups

Other bias

Low risk


Laine 1996 Methods

Single-centre, RCT

Participants

Country: USA. 150 patients with H. pylori infection by UBT and histology or serologic test for anti-H. pylori antibodies (UBT performed in patients who had EGD and histological evidence of H. pylori infection or had been screened with a rapid qualitative serological test for H. pylori antibodies)

Interventions

Omeprazole 20 mg bid, amoxicillin 1 g bid, and clarithromycin 500 mg bid for 7, 10 or 14 days (n=50 per group)

Outcomes

H. pylori eradication rate after 4 weeks determined by UBT; adverse events





“using a computer-generated randomization sequence”



Unclear risk


No information was provided. It is unclear whether patients and physicians were blinded


124

Laine 1996

(Continued)


No information was provided. It is unclear whether outcome assessors were blinded (for UBT)


Low risk

Eradication rate reported in ITT and PP sample, only one patient lost to follow up, it is unlikely to have impact on the efficacy analysis between groups


Low risk

Reported patients’ number with any adverse events. However, detail for individual adverse events was not provided. Only one patient lost of follow up, it is unlikely have impact on the adverse event analysis between groups


Low risk


Other bias

Low risk


Lee 2004 Methods

Multicentre, double-blind, RCT

Participants

Country: South Korea. 770 patients with PUD andH. pylori infection (confirmed by RUT and histology)

Interventions

Oral PPI (omeprazole 20 mg or pantoprazole 40 mg or rabeprazole 10 mg or esomeprazole 40 mg) bid, clarithromycin 500 mg bid and amoxicillin 1 g bid for 1 week (n=328) or 2 weeks (n=342)

Outcomes

H. pylori eradication after 4 weeks assessed by UBT

Notes

Different PPIs were used, rabeprazole was low dose only 10mg bid. No raw data was reported for different PPIs, this study was put in the standard dose subgroup

Risk of bias Bias




”randomized“ However, the randomisation method was unclear. It is unclear whether it was randomised to different PPIs first then randomised to different duration. Sample size was imbalanced. Conference proceedings


No information was provided. Conference proceedings.

Unclear risk


125

Lee 2004

(Continued)


”double blind“ study. However, it is unclear how double-blind was achieved because PPIs used were different, whether each centre used the same PPI


It is not reported whether outcome assessors were blinded (for UBT). However, based on the doubleblind study design, the outcome assessors were likely blinded


Unclear risk

Reported eradication data in ”enrolled“ patients, we presumed it was the ITT sample. It is unclear how many patients discontinued treatment due to adverse events or dropouts


Unclear risk

No raw data for adverse events except ”no difference in side-effects between both groups“


Unclear risk

Conference proceeding, it is unclear whether adverse event was one of the planned outcome

Other bias

Unclear risk


Louw 1998a Methods

Single-centre, Single-blind, RCT

Participants

Country: South Africa. 62 patients with uncomplicated DU or pylori channel ulceration and H. pylori infection (determined by positive RUT then confirmed by histology)

Interventions

Lansoprazole 30mg od, amoxicillin 1 g bid and clarithromycin 500 mg bid for 7 or 14 days. All patients received lansoprazole for 14 days. Patients who had unhealed ulcer or symptomatic at 14 day endoscopy were treated with lansoprazole 30 mg od for a further 14 days

Outcomes

H. pylori eradication 4 weeks after cessation of all therapy (determined by RUT and histology), ulcer healing and adverse events

Notes

Authors used ITT-KPA (ITT-Key point available) that excluded 4 patients (2patients >65 year and 2 patients negative histology after positive RUT, all from 7 days group) after randomisation, in the analysis of eradication. We first used randomised sample as ITT analysis, then in the sensitivity analysis was performed by using the data for ITTKPA data provided by authors. (Fuccio 2007 used ITT-KPA data in their meta-analysis) . In contrast, the authors used randomised ITT to report the adverse events

Risk of bias


126

Louw 1998a

(Continued)

Bias




“randomized to”, no information provided for randomisation method



Unclear risk


Single blind study, only investigators were blinded.


It is unclear whether outcome assessors were blinded. Considering the investigators were blinded, it is likely the outcome assessors were blinded


Unclear risk

Eradication was reported in the ITT-KPA sample. Authors excluded some patients that did not meet the inclusion criteria after the randomisation; however, all excluded patients came from the same 7 days group. If we use randomised sample as ITT and considered all these excluded patients failed eradication, bias might be introduced, therefore we performed sensitivity analysis using both ITT and ITT-KPA provided by authors


Unclear risk

The authors used ITT-KPA to reported eradication rate. In contrast, the authors used randomised ITT to report the adverse events. The adverse event rate might be underestimated, if considered all excluded patients had no adverse events.Two patients lost to follow up, but it is unclear from which group, although it is unlikely have impact on the adverse event analysis


Low risk


Other bias

Low risk


Louw 1998b Methods

Multicentre, single-blind RCT

Participants

Country: South Africa. 67 patients with DU and H. pylori infection determined by RUT, histology and culture (only positive RUT required for enrolment)


127

Louw 1998b

(Continued)

Interventions

Pantoprazole 40mg bid, amoxicillin 1g bid and clarithromycin 500mg bid for 7 days or 14 days. All patients received pantoprazole for 14 days. Unhealed DU associated with dyspeptic symptoms received pantoprazole 20mg od for further 2 weeks (no patient needed that). Antacids were allowed

Outcomes

H. pylori eradication 4 weeks after stopping all medications (determined by histology and culture), ulcer healing, antibiotics resistance before and after treatment, adverse events

Notes

Authors stated ”excluded previous failed treatment with a clarithromycin -containing regimen“ but not clear whether previous other H. pylori regimens were allowed. Authors’ ITT included patients took at least one dose In 43 patients had available results, no stains were found to be resistant to clarithromycin and amoxicillin, in the only two patients had results after therapy, secondary resistance was not noted

Risk of bias Bias




“randomization using a computer-generated randomization list”


Unclear risk

Used “a sealed envelope in blocks of four”. Did not mention whether the envelopes were opaque and in sequence numbers


“Single blind” study, it is unclear which party was blinded.


It is unclear whether the outcome assessors (for history and culture) were blinded to the assignment


Low risk

Eradication rate reported in ITT sample, ITT&KPA (ITT and key point available) and PP sample. Figure 1 provided detail for patients did not complete treatment


Low risk

Adverse events were reported for the ITT population. 3 vs 1 patient lost to follow up, it is unlikely to have impact on the adverse event analysis


Low risk


Other bias

Low risk



128

Lv 2011 Methods

Multiple-centre RCT.

Participants

Country: China. 580 DU patients with H. pylori infection.

Interventions

Patients were randomised to: rabeprazole 10 mg, amoxicillin 1000 mg, furazolidone 100 mg bid for 7 or 10 days; or, rabeprazole 10 mg, bismuth 220 mg, amoxicillin 1000 mg, furazolidone 100 mg, bid for 7 or 10 days (n=145 per group)

Outcomes

H. pylori eradication 4 weeks after treatment completion by the UBT test

Notes

Conference proceeding. Method to assess H. pylori infection before eradication was not clear. We presume it was ”UBT“, because H. pylori was re-assessed by UBT after therapy.

Risk of bias Bias




“randomly assigned”, no other information was provided.


Unclear risk







Low risk

542 out of 580 patients completed the therapy. H. pylori eradication reported in ITT sample and PP sample.


Unclear risk

Only 542 out of 580 patients completed the therapy. No information provided for lost of follow up or adverse event, because conference proceeding


Unclear risk

Conference proceeding. Did not report adverse event and it is unclear whether adverse event was one of the planned outcome

Other bias

Unclear risk



129

Maconi 2001 Methods


Participants

Country: Italy. 142 patients with DU or FD and H. pylori infection (determined by UBT and subsequently confirmed by histology)

Interventions

Lansoprazole 30mg bid, clarithromycin 500mg bid, and amoxicillin 1g bid for 1 or 2 weeks. Antacids were allowed after eradication therapy

Outcomes

H. pylori eradication assessed by UBT both at 1 month and 3 month (both tests negative) , effect of prognostic factors on eradication rate, primary antibiotics resistance, adverse events

Notes

1. Several tests were performed before eradication but only two were required for eligibility 2. Data for DU patients are available in Maconi 2000 study published in Digestive Liver Disease. We then calculated the data for FD patients based on the eradication rate in overall ITT sample 3. Primary resistance (based on 56 patients) to clarithromycin and amoxicillin was observed in 10.7% and 0% of patients, respectively

Risk of bias Bias




“randomized to…(two lists of randomisation one for duodenal ulcer patients and one for those with functional dyspepsia).”, no information provided for randomisation method



Unclear risk


“open label study”, patients and physicians were not blinded


Open-label study. However, it is unclear whether the outcome assessors (eg. lab technicians) for H. pylori eradication were aware of the treatment patients received. The assessment for H. pylori eradication is unlikely to have been impacted by the open-label design


Low risk

Eradication was provided in ITT and PP sample. Patients discontinued the treatment was reported and balanced between the two groups


Low risk

Patients with adverse events were reported in ITT sample; only 1 vs 2 patients discontinued treatment. It is unlikely to have impact on the adverse event analysis


130

Maconi 2001

(Continued)


Low risk


Other bias

Low risk


Mantzaris 1999 Methods

Single-centre RCT

Participants

Couintry: Greece. 403 patients with PUD and H. pylori infection (by RUT, histology and immunohistochemistry). 219 patients were included in this meta-analysis

Interventions

Omeprazole 20 mg bid, amoxicillin 1 g bid, clarithromycin 500 mg bid for 7 (n=86), 10 (n=78) or 14 days (n=55). Other treatment groups were: OCM x7 days (n=43), OAM x14 days (n=70) or OBMT x 10 days (n=71)

Outcomes

H. pylori eradication after 8 weeks by RUT, histology and immunohistochemistry, adverse events

Notes

It is unclear whether the authors used PP sample size to calculate the adverse events and ITT sample size to calculate the compliance rate, because based on the provided percentage, the sample size used for side effects and compliance for OAC14 was not consistent with other groups. Imbalanced sample size, it is unclear whether it was a real randomised trial

Risk of bias Bias




“randomized”, conference proceeding, no information was provided. However, the sample size was imbalanced between groups, whether real RCT is questionable


Conference proceeding, no information was provided.

Unclear risk


Conference proceeding, no information was provided. It is unclear whether any party was blinded


Conference proceeding, no information was provided. It is unclear whether outcome assessors were blinded


Eradication rate reported both in ITT and PP sample. However, it is unclear why patients were excluded from PP analysis, and how many patients lost to follow up or discontinued treatment due to adverse events. Although ITT sample was imbalanced, PP sample size was 88% to 89% of the ITT sample in three eligible

Low risk


131

Mantzaris 1999

(Continued)

groups, therefore it was balanced and unlikely has impact on the treatment effect estimate Incomplete outcome data (attrition bias) Adverse Event

High risk

Adverse events were reported. However, it is unclear whether the analysis was based on PP sample (the percentage of OAC14 group does not match the provided patient number and PP sample size); and whether patients discontinued treatment due to adverse events were counted. To be consistent, we used PP sample size for all adverse event analyses


Low risk

Conference proceeding, but expected outcomes were reported.

Other bias

Unclear risk


Mesquita 2005 Methods


Participants

Country: Brazil. 120 patients with PUD (active or healed) and H. pylori infection (determined by RUT and histology)

Interventions

Ranitidine bismuth citrate 400 mg bid and clarithromycin 500 mg bid for 1 or 2 weeks. RBC used 4 weeks in both groups

Outcomes

H. pylori eradication after 12 weeks of treatment determined by RUT and histology; ulcer healing, new detected erosive oesophagitis at follow up EGD; adverse events





“randomized”, no detail information was provided for eradication method



Unclear risk


“open study”, physicians and patients were not blinded.


Open study. However, it is unclear whether the outcome assessors (eg. lab technicians, pathologist) for H. pylori eradication were aware of the treatment patients received. The assessment for H. pylori eradication is unlikely to have been impacted by the open-label design


132

Mesquita 2005

(Continued)


Low risk

Eradication was reported in ITT and PP sample. 11 patients lost to follow up, they were balanced between two groups, it is unlikely to have impact on the efficacy analysis


Low risk

Patients with adverse events were reported for both groups. It is unclear whether any of the lost to follow up patients discontinued treatment due to adverse events, but the lost to follow up were balanced between two groups. It is unlikely to have impact on the adverse event analysis


Low risk


Other bias

Low risk


Moayyedi 1996 Methods


Participants

Country: UK. 73 patients (duodenitis, oesophagitis, hiatal hernia, normal or others under EGD) with H. pylori infection determined by UBT and RUT (histology and culture were also performed)

Interventions

Lansoprazole 30mg bid, amoxicillin 1g bid, clarithromycin 500mg bid for 1 or 2 weeks

Outcomes

H. pylori eradication after 4-6 weeks assessed by UBT, primary antibiotics resistance, adverse events

Notes

1.Authors excluded three patients lost to follow-up in the analysis, we calculated the eradication rate in the randomised sample. Authors’ defined analysed sample size was used in the sensitivity analysis 2. One patient from each group had previously received bismuth salt+antibiotic to cure H. pylori but failed. Adverse events reported differently in results and discussion 3. Metallic taste and glossitis reported separately in this study, we combined the two events in this meta-analysis (presumed they were not reported by the same patients), then performed sensitivity analysis by only using the data from metallic taste (presume some patients had both events) 4. In this study, 1.6% (1/64) stains resistant to clarithromycin pre-treatment, 6/7 failure patients developed secondary resistance to clarithromycin. All stains remained sensitive to amoxicillin before and after treatment

Risk of bias Bias



Support for judgement “randomized”, no information was provided for randomisation method


133

Moayyedi 1996

(Continued)


Unclear risk



“This was conducted as an open study so that any benefits of improved compliance in taking a 1-week regimen would be observed”, patients and physicians were not blinded. “the patient and doctor assessing adverse events were aware of the length of treatment”


“The treatment group was blinded to the assessment of H. pylori status”. It is likely outcome assessors were blinded (for UBT)


Low risk

Eradication was reported in patients that followed up. Patient who lost to follow up (2 vs 1) were excluded in their ITT analysis by the authors. We were able to use real ITT sample in the analysis. It is unlikely that the loss to follow up has impact on the efficacy analysis


Unclear risk

Adverse events were reported in patients who had followed up. 55% vs 84% patients had adverse events. However, the numbers were different compared to that quoted in the discussion (48% vs 78%)


Low risk


Other bias

Low risk


Mones 1997 Methods

Single-centre RCT

Participants

Country: Spain. 126 patients with DU and H. pylori infection (by UBT, RUT or histology)

Interventions

Omeprazole 20 mg bid, amoxicillin 1 g bid, clarithromycin 500 mg bid for 1 (n=65) or 2 weeks (n=61)

Outcomes

H. pylori eradication after 4-6 weeks assessed by UBT

Notes

58 more patients were included in 7 days group after randomisation, we did not included the data from these not-randomised patients

Risk of bias Bias




134

Mones 1997

(Continued)


“randomized”, on information was provided for randomisation method. Conference proceeding


Unclear risk

No information was provided. Conference proceeding.






Unclear risk

We presumed “enrolled patients” referred to all randomised patients. It is unclear whether any patients lost to follow up and whether it has impact on the effect analysis. Conference proceeding


Unclear risk

Adverse events were reported in all enrolled patients. It is unclear whether any patients discontinued therapy due to adverse events. Conference proceeding


Low risk

Conference proceeding, but expected outcomes were reported.

Other bias

Unclear risk


Muszynki 1992 Methods

Single-centre, RCT

Participants

Country: Poland. 42 patients with FD and H. pylori infection (determined by RUT and histology)

Interventions

Bismuth Subsalicylate 250 mg bid, tetracycline 500 mg bid and metronidazole 250 mg bid for 7 (n=21) or 14 days (n=21)

Outcomes

H. pylori eradication after 4 weeks determined by RUT and histology, inflammation, clinical symptom, adverse events





135

Muszynki 1992

(Continued)


“randomized”, no detail information was provided for randomisation method


Unclear risk







High risk

Eradication data was reported in PP sample after excluding those lost to follow up and those had discontinued treatment “due to intolerance”. We were able to calculate the eradication rate in ITT. The lost to follow up was imbalanced (4 vs 1), which can have impact on treatment effect estimate


High risk

Adverse event was reported in patients except those had lost to follow up. It is unclear whether any of the lost to follow up patients discontinued treatment due to adverse events. The lost to follow up was imbalanced (4 vs 1). We used the ITT sample to analysis the adverse events


Low risk


Other bias

Low risk


Nakagawa 1999 Methods


Participants

Country: Japan. 106 patients with PUD and H. pylori infection (determined by UBT, RUT or histology)

Interventions

Lansoprazole 30 mg od, amoxicillin 750 mg bid, clarithromycin 400 mg bid for 1 (n= 60) or 2 weeks (n=46). All patients received lansoprazole 30 mg od x 4 weeks after eradication regimens

Outcomes

H. pylori eradication 4 weeks after completion of therapy (assessed by UBT and RUT and histology), adverse events. H. pylori recurrence after 6 months and 1 year, ulcer recurrence.

Notes Risk of bias Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

136

Nakagawa 1999

(Continued)

Bias




“randomized”, no detail information was provided for randomisation method. However, sample size was imbalanced between the two groups



Unclear risk






Low risk

Eradication was reported in ITT and PP sample. Both groups had 4 patients lost to follow up, it is unlikely have impact on the efficacy analysis


Low risk

Adverse events were reported in ITT sample, patients discontinued treatment due to adverse events were reported. 4 vs 4 patients lost to follow up, it is unlikely have impact on the adverse events analysis


Low risk


Other bias

Low risk


Palmas 2002 Methods

Single-centre RCT

Participants

Country: Italy. 172 patients with H. pylori infection (determined by histology and UBT) and history of recurrent DU

Interventions

A standard dose of PPI, amoxicillin 1 g bid and clarithromycin 500 mg bid for 7 days (n=66) , 10 days (n=42) or 14 days (n=64)

Outcomes

H. pylori eradication after 4 weeks determined by histology and UBT.

Notes

”standard dose PPIs“ but no detail. Both ”14 days“ and ”15 days“ were used in the abstract and text, we presume ”15 days“ was a typo for ”14 days“


137

Palmas 2002

(Continued)

Risk of bias Bias




“randomly treated”, no information was provided for the method of randomisation. The same size was imbalanced between groups


Unclear risk







Unclear risk

The authors did not use the term “ITT”, it is unclear whether any patients lost of follow up; we assumed the eradication rate was reported in all patients were randomised


Unclear risk

Did not report adverse events, except “side effects infrequent and mild”


High risk

Did not report adverse events except “side effects infrequent and mild”; recorded DU recurrence but did not report the outcome data

Other bias

Low risk


Paoluzi 1998 Methods

Single-centre, single-blind, RCT

Participants

Country: Italy. 209 patients with FD and H. pylori infection (determined by histology)

Interventions

Patients were randomised to eight groups: lansoprazole 30 mg bid, clarithromycin 500 mg bid and metronidazole 500 mg bid for 1 (n=27) or 2 weeks (n=25), lansoprazole 30 mg bid, clarithromycin 500 mg bid and amoxicillin 1 g bid for 1 (n=26) or 2 weeks (n=26), omeprazole 20 mg bid, clarithromycin 500 mg bid, metronidazole 500 mg bid for 1 (n=27) or 2 weeks (n=23), omeprazole 20 mg bid, clarithromycin 500 mg bid, amoxicillin 1 g bid for 1 (n=28) or 2 weeks (n=27). All PPIs used for 2 weeks

Outcomes

H. pylori eradication 8 weeks and 24 weeks from start of therapy assessed by histology


138

Paoluzi 1998

(Continued)

Notes

Contacted the author and confirmed that they only included ”naive“ patients. (this study was excluded by Fuccio 2007 due to ”not first line therapy“ which seems was a mistake). The author also confirmed the data from this study was not published in the 2001 abstract or 2006 paper The authors provided information on H. pylori assessment method (should be histology, original text was ”endoscopy proven“)

Risk of bias Bias




“randomly assigned”, no detail information was provided for the randomisation method



Unclear risk


“single blind”, it is unclear whether physicians or patients were blinded. Based on the Paoluzi 2006 from the same group, it is likely that investigators were blinded


No information was provided whether the outcome assessors were blinded (for histology)


Low risk

Eradication was provided in ITT number. Patients dropped out were reported. We considered all dropped out patients failed eradication


Unclear risk

Adverse events were not reported. It is not clear whether any patients discontinued treatment due to adverse events


Unclear risk

Conference proceedings, it is not clear whether adverse event was a planned outcome

Other bias

Unclear risk


Paoluzi 2006 Methods

Single-centre, single-blind, RCT.

Participants

Country: Italy. 486 patients (PUD or FD or GERD) with H. pylori infection (determined by UBT and histology)


139

Paoluzi 2006

(Continued)

Interventions

Omeprazole 20 mg bid, clarithromycin 500 mg bid, amoxicillin 1 g bid for 1 (n=117) or 2 weeks (n=126); omeprazole 20 mg bid, clarithromycin 500 mg bid, metronidazole 500 mg bid for 1 (n=122) or 2 weeks (n=121)

Outcomes

H. pylori eradication 8 weeks after completion of therapy assessed by UBT and histology, prognostic factors for eradication rate; adverse events





“Computer-generated randomized schedule”.



Unclear risk


Single blinded, only investigators were blinded.


Since investigators were blinded, it is likely that outcome assessors were blinded (for UBT and histology)


High risk

Eradication was reported in ITT and PP sample, 75 (15%) of the patients dropped out and was imbalanced between 4 groups (10-21%). Reasons for exclusion in PP sample was provided for overall patients but not separating for groups


High risk

Adverse events were reported after excluding patients had lost to follow up, 32 patients lost to follow up without separating for groups. The adverse events were combined for 1+2 weeks group. 23 patients withdrew due to adverse events but it was combined for all groups. Therefore, no analysis was possible for comparing 1 and 2 weeks


High risk

Adverse events were reported after excluding patients had lost to follow up, However, it was combined for 1+2 weeks group, separated for OAC and OMC group. 23 patients withdrew due to adverse events but it was combined for all groups

Other bias

Low risk



140

Park 2009a Methods

Single-centre RCT.

Participants

Country: South Korea. 107 H. pylori infected patients, diagnosed with UBT, TRUT, or histology with endoscopic biopsy, 81 patients were included in this systematic review

Interventions

Patients were randomly allocated into PPI+amoxicillin 1 g +clarithromycin 500 mg bid for 7 days (n=25) or 10 days (n=27) or 14 days (n=29) , or a sequential regimen group (rabeprazole 20 mg+amoxicillin 1 g bid for 5 days, followed by rabeprazole 20mg+clarithromycin 500 mg +tinidazole 600 mg bid for 5 days) (n=26). Type and dose of PPI is not clear

Outcomes

H. pylori eradication that checked with any of the tests used for diagnosis at least 4 weeks after finishing the treatment; adverse events

Notes

Type and dose of PPI is not clear. For adverse event, only reported detail for the sequential group, then stated as ”There was no significant difference of side effects among four groups“, no detail for the triple therapy groups

Risk of bias Bias




”randomly allocated into four groups“. No detail information was provided


Unclear risk

Conference proceeding. No detail information was provided.






Low risk

All patients completed the therapy. H. pylori eradication rate reported in all patients.


Unclear risk

All patients completed the therapy. No detail was given for adverse events for triple therapy group, except “no significance of side effects among four groups”


Unclear risk

Side effects were only reported for sequential group. It is not clear whether no side effect was reported in the triple therapy group

Other bias

Unclear risk



141

Pellicano 2002 Methods

Single-centre RCT

Participants

Country: Italy. 159 patients with a history of recurrent DU and H. pylori infection determined by UBT and histology.

Interventions

A standard dose of omeprazole bid, amoxicillin 1 g bid and metronidazole 500 mg bid for 7 or 10 or 14 days (n=53 each group)

Outcomes

H. pylori eradication after 4 to 6 weeks determined by UBT and histology

Notes

”standard dose omeprazole“ was stated. Authors planned to exclude patients who did not take any study from the ITT and PP analyses. It is unclear whether any patients were excluded because no drug was taken. Based on the identical sample size of the three groups, it is likely that no patients were excluded from ITT analysis

Risk of bias Bias




“Randomly treated”, no information was provided for the method of randomisation


Unclear risk







Low risk

Eradication was provided in ITT and PP sample size. However, authors planned to exclude patients who did not take any study from the ITT and PP analyses. It is unclear whether any patients were excluded because did not take any drugs. Based on the identical sample size of the three groups, it is likely that no patients were excluded from ITT analysis


Unclear risk

Adverse events were not reported except ”frequency of adverse events were evenly distributed between the groups“. Patients who discontinued treatment due to adverse events were reported


High risk

Adverse events were not reported except ”frequency of adverse events were evenly distributed between the groups“

Other bias

Low risk



142

Pozzato 1998 Methods


Participants

Country: Italy. 112 patients with active DU and H. pylori infection determined by UBT, RUT and histology (at least 2 positive)

Interventions

RBC 400 mg bid clarithromycin 500 mg bid for 7 days (n=56) or 14 days (n=56). RBC used for 4 weeks in both groups

Outcomes

H. pylori eradication 4 weeks after completion of therapy assessed by UBT, RUT and histology (at least two tests available then all tests negative), DU healing, factors related to ulcer healing and H. pylori eradication rate; adverse events.

Notes

Authors’ ITT sample referred to randomise patients received at least one dose. It is unclear whether any patient was excluded from the ITT analysis due to not taking any medication

Risk of bias Bias




“randomized to receive”, no detail information was provided for the method of randomisation



Unclear risk


“open study”, patients and physicians were not blinded.




Low risk

Eradication was provided in ITT and PP sample. ITT included randomised patients who took at least one dose. It seems more patients withdrawn in 7 days vs 14 days group (6 vs 1). Reasons for withdrawal was given in table 2, and only one of them were due to lack of efficacy


Low risk

Adverse events were reported in randomised patients. Patient who discontinued treatment due to adverse events were reported


Low risk



143

Pozzato 1998

(Continued)

Other bias

Low risk


Riquelme 2007 Methods

Single-centre, open, quasi-randomisation (by ID number)

Participants

Country: Chile. 131 subjects (with PUD or erosive non-ulcer disease or normal EGD) with H. pylori infection determined by RUT

Interventions

Omeprazole 20 mg bid, amoxicillin 1 g bid and clarithromycin 500 mg bid for 7 (n= 69) or 14 days (n=62)

Outcomes

H. pylori eradication after 6 weeks determined by RUT. Impact of smoking, erosive nonulcer disease and pervious antibiotic exposure on eradication rate; adverse events

Notes

Quasi-randomization, by the last digital of patient’s ID number Data was reported for patients with PUD, erosive non-ulcer disease and normal endoscopy. Authors named erosive non-ulcer disease as ”FD“ including superficial mucosal defects might be seen in the gastric or duodenal mucosa or oesophageal mucosa. Because all included patients had dyspepsia or abdominal pain, we grouped data for ”erosive nonulcer disease“ and ”normal“ patients into ”FD“ group in the subgroup analysis

Risk of bias Bias




“quasi-randomized, by means of the last digit of the identification number: odd numbers were assigned to the 7 days group and even numbers to the 14 days group”


High risk

Due to the study was a quasi-randomised trial, the physician can predict the next patient would enrol in which group




Open study. However, it is unclear whether the outcome assessors (for RUT) for H. pylori eradication were aware of the treatment patients received. The assessment for H. pylori eradication is unlikely to have been impacted by the open-label design


144

Riquelme 2007

(Continued)


High risk

Eradication was reported in ITT and PP sample. Patient numbers that lost to follow up and discontinued treatment due to adverse events were provided. More patients lost to follow up in 7 days group (6 vs 2) . It is unclear whether the imbalance withdrawal has impact on the treatment effect estimate


High risk

Adverse events were reported in ITT sample, individual adverse events were reported. More patients lost to follow up in 7 days group (6 vs 2), these lost to follow up (6%) have impact on adverse events analysis


Low risk


Other bias

Low risk


Robles-Jara 2008 Methods


Participants

Country: Ecuador. 136 patients with dyspepsia (normal mucosa or gastritis or PUD) and H. pylori infection determined by RUT and histology

Interventions

Omeprazole 20 mg bid, clarithromycin 500 mg bid, amoxicillin 1 g bid for 7 days or 10 days

Outcomes

H. pylori eradication after 8 weeks determined by histology; histology assessment (gastric mucosa inflammatory inactivation)

Notes

Authors’ ITT excluded patients that did not return for follow-up. We presume these patients failed H. pylori eradication.

Risk of bias Bias




“Prospective, randomized, open-label study”, “randomized in a 1 :1 ratio”, no further information was provided



Unclear risk


145

Robles-Jara 2008

(Continued)


“open-label” study. Physicians and patients were not blinded


Open-label study. However, it is unclear whether the outcome assessors (eg. lab technicians, pathologist) for H. pylori eradication were aware of the treatment patients received. The assessment for H. pylori eradication is unlikely to have been impacted by the open-label design


High risk

Eradication was reported in authors’ defined ITT and PP analyses. Primary authors excluded 9 patients that lost to follow up in their ITT analysis; which was imbalanced between 10 days (n=6) and 7 days group (n=3). We used all randomised patients as the ITT sample size and presumed these lost to follow up patients had failed H. pylori eradication. The imbalance of lost to follow up (9% vs 4%) might have impact on the treatment effect estimate


Unclear risk

Adverse events attributed to non-compliance were reported for 10 days group in ITT sample. Although no non-compliance patients were found in the 7 days group, the author did not report whether any adverse events were reported in 7 the days group


High risk

Adverse events attributed to non-compliance were reported for 10 days group in ITT sample. The author did not report whether any adverse events were reported in 7-day group

Other bias

Low risk


Sacco 2010 Methods


Participants

Country: Italy. 399 patients with dyspepsia symptoms, with H. pylori infection (confirmed by UBT) randomised to 4 groups. 7 of them found to have active DU. 196 patients were included in this systematic review

Interventions

Esomeprazole 20 mg + amoxicillin 1 g + moxifloxacin 400 mg, twice daily for 5 days (n= 98), 7 days (n=102), or 10 days (n=94); esomeprazole 20 mg twice daily + amoxicillin 1 g twice daily + moxifloxacin 400 mg, once daily for 10 days (n=105)

Outcomes

H. pylori eradication assessed by UBT two months after the end of therapy; adverse event, rescue therapy


146

Sacco 2010

(Continued)

Notes

Randomized to three arms in the conference abstract (Sacco 2008), but become 4 arms in the full paper. Authors used PP sample when analysing adverse events which have excluded the patients dropped out due to adverse events, so the correct PP sample size for adverse event analysis should be 97 for the EAM800 10 days group

Risk of bias Bias




“randomly assigned to…” “following a computer generated List”



Unclear risk


Open trial. Physicians and patients were not blinded.


Open study. However, it is unclear whether the outcome assessors (eg. lab technicians, ) for H. pylori eradication were aware of the treatment patients received. The assessment for H. pylori eradication is unlikely to have been impacted by the open-label design


Low risk

H. pylori eradication rate provided in ITT as well as PP sample. Numbers for loss of follow up and drop out due to adverse events were provided


Low risk

Detail for adverse event provided as event number, the total event number is not the same as total patient number. However, the PP sample used by the authors have excluded the patients dropped out due to adverse events, so the correct PP sample size for adverse event analysis should include those patients, which we were able to get the number from table 1


Low risk


Other bias

Unclear risk

Randomized to three arms in the conference abstract (Sacco 2008), but become 4 arms in the full paper.


147

Savarino 1999 Methods


Participants

Country: Italy. 165 patients with FD and H. pylori infection determined by RUT and histology

Interventions

RBC 400mg bid, clarithromycin 250 mg bid and metronidazole 500 mg bid for 4, 7 or 10 days (n=55 in each group). Antacids were allowed

Outcomes

H. pylori eradication at least 4 weeks after stopping treatment determined by UBT; adverse events

Notes

ITT sample included patients received at least one dose. It seems no patient was excluded because did not take any drugs. Adverse events included events occurred during the course and the subsequent 30 days. We contacted the authors, adverse events were reported in ITT sample

Risk of bias Bias




“computer-generated randomization sequence with a 1:1 ratio”



Unclear risk






Low risk

Eradication was reported in ITT and PP sample. Dropped out reasons were provided and dropped out numbers were balanced between the groups


Low risk

Adverse events were reported in ITT sample. Dropped out reasons were provided included patients who discontinued treatment due to adverse events. Dropped out patients were balanced between the groups


Low risk


Other bias

Low risk



148

Scaccianoce 2006 Methods


Participants

Country: Italy. 213 patients with FD and H. pylori infection (determined by RUT and histology). 141 patients were included the analysis in this systematic review

Interventions

Esomeprazole 20 mg bid, clarithromycin 500 mg bid and amoxicillin 1 g for 7 days (n=70) or 10 days (n=71), or the 10 days sequential regimen (esomeprazole 20 mg + amoxicillin 1 g for 5 days then esomeprazole 20 mg bid, clarithromycin 500 mg bid and tinidazole 500 mg bid for the remaining 5 days) (n=72)

Outcomes

H. pylori eradication 4-6 weeks after completion of therapy assessed by UBT, impact of bacterial density on eradication rate; adverse events

Notes

We consider esomeprazole 20mg bid as standard dose.

Risk of bias Bias




“randomly assigned using a computer-generated list”



Unclear risk




Open study. However, it is unclear whether the outcome assessors (eg lab technicians) for H. pylori eradication were aware of the treatment patients received. The assessment for H. pylori eradication is unlikely to have been impacted by the open-label design


Low risk

Eradication was reported in ITT and PP sample. Dropped out reasons were provided and dropped out numbers were balanced between the groups


Low risk

Adverse events were reported in ITT sample. Dropped out reasons were provided and dropped out numbers were balanced between the groups


Low risk


Other bias

Low risk



149

Scaccianoce 2008 Methods

Two-centre; open, RCT

Participants

Country: Italy. 65 patients with dyspepsia, H. pylori infection confirmed by histology (Giemsa staining) jointly with an active chronic gastritis (HE) (only two arms with 32 patients were included in the meta-analysis)

Interventions

Lansoprazole 30 mg bid, clarithromycin 500 mg bid, amoxicillin 1 g bid (LAC), plus Probinul® (containing a probiotic mixture) 5 g/dose bid, for 7 and 14 days. (Another two arms that not included in the meta-analysis were LAC standard triple therapy for 7 days, LAC standard triple therapy plus Reuflor® containing L.reuteri 1 tablet bid for 7 days)

Outcomes

H. pylori eradication 4-6 weeks after treatment confirmed by UBT, adverse events

Notes

The paper itself did not use the word like ”random or randomisation“, but used ”prospective trial“. We contacted the authors and got response as ”RCT, computer generated list independently in the two participating centres“. Probinul® (containing a probiotic mixture) 5g/dose bid was used in both 7 days and 14 days arm. This was a pilot study, planned to include 30 patients per group. At the scheduled ”ad interim“ analysis, the enrolment of patients was censored for each group due to ITT eradication rate=grade 2, or culture positive)

Interventions

Lansoprazole 30 mg od for 2 weeks; plus amoxicillin 500 mg bid and clarithromycin 250 mg bid for 1 (n=55) or 2 weeks (n=57), the other three groups that not included in the meta-analysis were: LAM for 1 week (n=58), LCM (C250 mg bid) for 1 week (n= 62) or LAC (C500 mg bid) for 2 week (n=65)

Outcomes

H. pylori eradication after 4-6 weeks assessed by RUT, histology and culture (all negative) or UBT (if refused EGD), effect of metronidazole resistance and H. pylori pretreatment density on the eradication rate; adverse events

Notes

Lansoprazole used for 2 weeks in all groups. Primary resistance to metronidazole was 28.8% and resistance to clarithromycin was 3. 9%. Acquired resistance was reported in 7 patients in total Symptoms of adverse events were not recorded in the patients in one of the hospital

Risk of bias Bias




“randomly allocated”, no information was provided for randomisation method


Unclear risk







Eradication data was reported in PP sample. We calculated the eradication in ITT sample. The dropouts were higher in the 7 days (18%) than that in the 14 days group (12%).The imbalance of patients who have no outcome data might have impact on the treatment effect estimate

High risk


157

Yang 1999

(Continued)


High risk

Symptoms of adverse events were not recorded in the patients in one of the hospital; Therefore, adverse events were only available for 239 out of 297 patients, and analysed sample size was not provided for each group. We could only use PP sample in the analysis. Therefore, 20% of patients had missing outcome data which might have impact on the adverse event analysis


Low risk


Other bias

Low risk


Zagari 2007 Methods

Multicentre, double-blind, RCT.

Participants

Country: Italy. 909 patients with symptomatic DU and with H pylori infection (randomised according positive RUT then must be confirmed by UBT or histology). 604 patients were included in this systematic review

Interventions

Omeprazole 20mg bid for 2 weeks and amoxicillin 1 g bid and clarithromycin 500 mg bid for 1 week (n=302) or 2 weeks (n=302), or omeprazole 20 mg bid and amoxicillin 1 g bid for 2 weeks (n=305)

Outcomes

H. pylori eradication 4 weeks after completion of therapy assessed by UBT and histology, DU healing, adverse events

Notes

Authors’ ITT included patients with H. pylori infection and confirmed by other test and took ≥1dose after randomisation, we used randomised patients as the ITT sample in eradication analysis, and used authors’ defined ITT sample (1 patient from each group was excluded) in the sensitivity analysis. Omeprazole was used for two weeks in both groups

Risk of bias Bias




“The computer-generated randomisation list was blocked by centre into blocks of size 2, the block size was unknown to the investigators.”


“Treatments were assigned to patients using numbered containers and the randomisation was centralised and implemented by AstraZeneca, Italy”

Low risk


158

Zagari 2007

(Continued)


“double blind”, patients and physicians were blinded, placebo was used to ensure double blind


Based on the nature of the double-blind study, outcome assessors were likely blinded to the treatment allocation


Low risk

Eradication rate was provided in ITT and PP sample, although authors excluded one randomised patient per group in their ITT sample due to “no treatment or H. pylori negative), we were able to use the randomised patients in the ITT analysis


Low risk

Adverse events were reported in all randomised patients except one did not take any drugs. Lost to follow up, low compliance and protocol violation were similar between groups


Low risk


Other bias

Low risk


Zheng 2009 Methods


Participants

Country: China. 133 patients with dyspepsia and H. pylori infection (RUT and histology)

Interventions

Randomized to pantoprazole 40 mg bid colloidal bismuth subcitrate 220 mg bid, metronidazole 400 mg tid tetracycline 750 mg bid (PBMT) for 7 or 10 days, or pantoprazole 40 mg bid, amoxicillin 1.0 g bid and clarithromycin 500 mg bid (PCA) for 7 days

Outcomes

H. pylori eradication (UBT) 4 weeks after completion of therapy, adverse events





“randomized to”, no detail information was provided.



Unclear risk


159

Zheng 2009

(Continued)


Open-label study. Physicians and patients were not blinded.


Open-label study. However, it is unclear whether the outcome assessors (eg lab technicians) for H. pylori eradication were aware of the treatment patients received. The assessment for H. pylori eradication is unlikely to have been impacted by the open-label design


Low risk

H. pylori eradication reported in ITT sample and PP sample size. One patient from the 7 days quadruple therapy group lost follow up, one patient from 7 days group and one patient from 10 days group stopped treatment due to adverse events


Low risk

One patient from the 7 days quadruple therapy group lost follow up. Reported one patient from 7 days group and one patient from 10 days group stopped treatment due to adverse events


Unclear risk

Reported H. pylori eradication and patients stopped treatment due to adverse events. However, data for individual adverse events was not reported, except ”all were mild-moderate and self-recovered.“

Other bias

Low risk


DU: duodenal ulcer; EGD: endoscopy; GU: gastric ulcer; FD: functional dyspepsia; PUD: peptic ulcer disease; RCT: randomised controlled trial; RUT: rapid urease test; UBT: urease breath test

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Aragona 2002

Preliminary data of Di Mario 2003a

Aragona 2003a


Aragona 2003b


Armuzzi 2001

Compared regimens were not the same


160

(Continued)

Basu 2009a

H.pylori eradication assessed two weeks post therapy. In addition, it seems it was the preliminary data of Basu 2011, although the later one claimed to assessed four weeks after therapy

Basu 2009b

H.pylori eradication assessed two weeks post therapy. In addition, it seems it was the preliminary data of Basu 2011, although the later one claimed to assessed four weeks after therapy

Bazzoli 1999

Preliminary data of Zagari 2007

Bazzoli 2000a


Bazzoli 2000b


Bell 1995

Not a randomised trial

Boudjella 2009

Not clear whether it was a randomised trial. Dose for metronidazole was different for 7 days and 10 days

Brecken 1999

Not the same regimens for 7 days vs 10 days

Calderon 2002

No raw data for ITT or PP sample, only provided eradication rate

Calvet 2000

Meta-analysis of 13 RCTs comparing 7 vs 10 vs 14 days PPI triple therapy

Calvet 2001

A cost-effectiveness analysis

Calvet 2004

Preliminary data of Calvet 2005a

Calvet 2005b

Preliminary data of Calvet 2005a

Cardelli 1997

Preliminary data of Pozzato 1998

Castro 2001

No raw data for ITT sample, only reported eradication rate in PP sample

Cerqueira 2011

Not a randomised trial, used historical control.

Chen 1995

Although label as ”RCT“, after patients were randomised to no drug or eradication group, patients were ”further divided into“ 1 week or 2 weeks group (not clear whether based on randomisation), and recurred ulcer from 1 week group all assigned to 2 weeks’ group. Eradication rate reported mixed all these patients although under 1 or 2 weeks group

Chen 1996a

No ITT sample available, eradication rate reported in PP sample

Chen 1996b

Can not exclude duplicate from Chen 1995, can not confirm whether a RCT except ”allocated to 3 groups“

Ching 1997

Preliminary data of Ching 1998

Choi 2006

No raw data available although contacted the authors


161

(Continued)

Chun 2010

Duplicate data of Park 2009a, Park 2009b

Daghaghzadeh 2005

Preliminary data of Daghaghzadeh 2007. In this abstract, no raw data for: ITT sample, time to assessed H. pylori eradication and H.pylori eradication criteria

Dammann 1997

Preliminary data of Dammann 2000

de Silva 2004

H.pylori eradication was assessed only two weeks after treatment completion

Di Caro 2001a

Preliminary data of Di Caro 2002a

Di Caro 2001b


Di Caro 2001c


Di Caro 2002b

Published in full in Di Caro 2002a

Di Mario 1999

Ineligible duration

Di Mario 2002


Di Mario 2003b


Flores 2010

A meta-analysis of 26 RCTs compared different durations of PPI triple therapy

Ford 2003

Systematic review and meta-analysis of different H.pylori eradication regimens

Fuccio 2007

Meta-analysis of 21 RCTs comparing different duration of PPI triple therapy

Gené 2006

A cost-effectiveness study but not a RCT

Giasi-Gonzalez 2004

Preliminary data of Garza González 2007

Gisbert 2005b

Preliminary data of Gisbert 2005a.

Greenberg 2011

Ineligible comparison: 14 days of lansoprazole, amoxicillin, and clarithromycin (standard therapy); versus 5 days of lansoprazole, amoxicillin, clarithromycin, and metronidazole (concomitant therapy); versus 5 days of lansoprazole and amoxicillin followed by 5 days of lansoprazole, clarithromycin, and metronidazole (sequential therapy)

Habu 1997

Preliminary data of Kiyota 1999

Hasan 2010

Ineligible comparison: omeprazole 2 Chi 20 mg + amoxicillin 2 Chi 1 g + bismuth subcitrate 4 Chi 120 mg for 2 weeks, with furazolidone 2 Chi 200 mg in the first week only; compared with the same regimen, except that 1 week of furazolidone was followed by 1 week of metronidazole in the second week

Herba 2009

Not a randomised trial. Data was collected using an existing database


162

(Continued)

Iwasaki 1997

No raw data for ITT or PP sample, only provided ”total sample size“ and eradication rate

Jung 2006

Not clear whether was a randomised trial, and no raw data for eradication rate

Jung 2008

A meta-analysis of 10 Korean RCTs

Kamberoglou 2001

Ineligible regimen: In all patients, clarithromycin 500 mg bid and metronidazole 500 mg bid were given for the first week

Kang 2000b

Duplicate of Kang 2000a

Karatapanis 2000

Preliminary data of Karatapanis 2011

Karatapanis 2005


Karatapanis 2007


Katicic 1996

Judged as duplicate or preliminary data of Katicic 1997 after discussion between reviewers

Katicic 2006

Confusing data: patients number, groups and rates are inconsistent between the text and table, questionable randomisation, no further information although contacted the authors. When the Filipec Kanizaj 2009 paper was published, we suspected that the data from Katicic 2006 is preliminary report for the Filipec Kanizaj 2009 paper.

Khu 2010

Not a randomised trial, a retrospective study.

Kim 2001

A meta-analysis of nine Korean RCTs

Knigge 1998

Preliminary data of Knigge 1999

Krause 1997

Preliminary data of Fennerty 1998

Labenz 1993

It was not a randomised study

Lamouliatte 1998

Preliminary data of Lamouliatte 2000

Lamouliatte 2000

It was not a real randomised trial, patients were put in two groups by calendar years

Lanza 2002

Preliminary data of Vakil 2004

Lee 1997

No raw data for sample size, maybe the preliminary data of Lee 2004b

Lee 1998

No raw data and could not retrieve full text

Lee 2004b

No raw data for key information although contacted the authors, also presume duplicate data of Keum 2005


163

(Continued)

Lee 2006


Liao 2002

Not a randomised trial, and combined different regimens

Lopez-Roman 2011

Ineligible regimen: compared two durations of sequential therapy

Maconi 1998

Preliminary data of Maconi 2001

Maconi 1999

Preliminary data of Maconi 2001

Makarenka 2004

Preliminary data of Makarenka 2005. No ITT eradication rate

Makarenka 2005

Only reported ITT sample but PP eradication rate without providing the PP sample size, therefore we were not able to calculate the ITT results

Matougui 2009

Ineligible regimen: dose of metronidazole in the 10 days group was higher then the dose in the 7 days group

Miwa 1998


Moayyedi 1995

Preliminary data of Moayyedi 1996

Nishikawa 1999

The authors did not mention whether it is a randomised trial

Ogura 2000

Not a randomised trial, pretreatment H.pylori assessing method is not clear

Ogura 2007


Oh 2006

No raw data only eradication rate, even contacted the authors

Oqura 2007

Not a randomised trial, patients were ”consecutively assigned to either the 7- or the 14-day group“ and the patients’ numbers were not balanced in two groups

Paoluzi 2001

Preliminary data of Paoluzi 2006

Park 2009b

Dupliate data of Park 2009a

Pimanov 2005

Duplicate data of Makarenka 2005

Rodionoff 1990

Was a reference of de Boer’s 1994 papers, no full text or abstract could be found

Rodríguez 2003

Eradication was determined by PCR only, except some samples also had culture

Rodríguez Téllez 1999

No eradication data in the text, even contacted the author

Rogha 2009

Ineligible comparison: dose for azithromycin were different in three arms: azithromycin 500 mg bid for 6 days + omeprazole 20 mg, amoxicillin 1 g, bismuth 240 mg all bid for 2 weeks; versus azithromycin 500 mg bid for 3 days + omeprazole 20 mg, amoxicillin 1 g, bismuth 240 mg all bid for 1 week versus azithromycin


164

(Continued)

250 mg bid for 3 days + omeprazole 20 mg, amoxicillin 1 g, bismuth 240 mg all bid for 1 week Sacco 2008

Preliminary data (conference proceeding) for Sacco 2010, however, only three arms in the abstracts but 4 arms in the full paper

Salandin 1995

Did not mention whether the patients were randomised

Schwartz 2002


Sharma 2002

Preliminary data of Chaudhary 2004

Simsek 2000

Preliminary data of Simsek 1999, except the H.pylori assessment time was different

Utzon 1994


Uygun 1999

Ineligible regimen: compared regimens were different

Vakil 2002a


Vakil 2002b


Vakil 2002c


Vakil 2002d


Vakil 2002e


Vakil 2002f


Vakil 2002g


Vakil 2002h


Vakil 2003a


Vakil 2003b


Vakil 2003c


Xiang 2007

Prediatrics study

Zhou 2009

Non a randomised trial

Zullo 2004

Preliminary data of Scaccianoce 2006


165

Characteristics of studies awaiting assessment [ordered by study ID] Chen 2013 Methods

Single centre, RCT, no information regarding blinding.

Participants

Country: China. 152 patients with H. pylori-positive (by RUT or histology or UBT, any one positive) chronic gastritis or duodenal ulcer

Interventions

Furazolidone-based quadruple therapy group (esomeprazole 20 mg + bismuth potassium citrate 220 mg + amoxicillin 1000 mg + furazolidone 100 mg bid) for 7 days (n= 48) or 10 days (n=51), versus control group (esomeprazole 20 mg + bismuth potassium citrate 220 mg +amoxicillin 1000 mg + clarithromycin 500mg bid) for 7 days (n=53)

Outcomes

H.pylori eradication (by UBT) assessed at least 2 weeks after cessation of PPI and 4 weeks after cessation of antibiotics; the rates of symptom remission and adverse events

Notes Choi 2012 Methods

Single centre, RCT, no information regarding blinding.

Participants

Country: South Korea. 460 patients with H. pylori -associated (by UBT, RUT and histology) gastritis or a gastric or duodenal ulcer

Interventions

Triple therapy (rabeprazole 20 mg + amoxicillin 1.0 g + clarithromycin 500mg bid) for 7, 10 or 14 days, or a sequential therapy for 10 days (amoxicillin 1.0 g + rabeprazole 20mg bid for the first 5 d, followed by rabeprazole 20 mg + clarithromycin 500 mg + tinidazole 500 mg bid for the remaining 5 days) (n=115 patients in each group)

Outcomes

H.pylori eradication assessed 4 week after treatment by UBT and histology

Notes Fallone 2013 Methods

Single centre study in which only some patients were randomized by the method of quasi-randomization (randomized according to day of visit). Physicians and patients were not blinded, but outcome assessors were blinded

Participants

314 patients with clinically acceptable indication for treatment of active H.pylori infection (by histology or UBT) , only subgroup of patients (n=172 from January 2009 to December 2011) were quasi-randomized to 7 (if odd number) or 14 days (if even number) according to day of visit

Interventions

Lantoprazole 30 mg, amoxicillin 1000 mg and clarithromycin 500 mg bid for 7 days (n=148) or 14 days (n=166). 172 patients were were quasi-randomized (n=76 vs 96)

Outcomes

H.pylori eradication (by UBT and histology) at least 4 weeks after completion of antibiotics, predictors of successful eradication


166

Fallone 2013

Notes

(Continued)

We will only include the data from the subgroup of quasi-randomized patients for this review due to thehigh risk of bias to random sequence generation

Konorev 2012 Methods

RCT

Participants

128 patients with duodenal bulb ulcer associated with H. pylori (histology and RUT)

Interventions

Omeprazole 0.04 g/day, clarithromycin 1 g/day, amoxicillin 2 g/day (OCA) for 7 days (n=33) or for 14 days (n=34) ; OCA for 7 days and Licopid 0.001 g/day for a day (n=34); and OCA and Licopid 0.01 g/day for 10 days (n=27)

Outcomes

H.pylori eradication 6-8 weeks after discontinuation of all drugs; gastric metaplasia

Notes

It was unclear from the abstract that whether this was an RCT, however this was confirmed to be an RCT by the study author. We are awaiting translation of this Russian paper for full study details. This is a single author study, which may increase the risk of bias

Lv 2013 Methods

Multiple-centre, RCT, no information regarding blinding

Participants

754 H. pylori positive patients, 376 with duodenal ulcer in 376 cases and 378 with chronic gastritis cases

Interventions

Esomeprazole, bismuth, amoxicillin and furazolidone twice daily for 10 or 7 days; or esomeprazole, amoxicillin and furazolidone twice daily for 10 or 7 days

Outcomes

H.pylori eradication

Notes

We need to contact authors for more information.

Prasertpetmanee 2013 Methods

Single centre, data pooled from two pilot studies, RCT, no information for blinding

Participants

Country: Thailand. 110 H. pylori-infected subjects (by culture; or two positive tests RUT and histology)

Interventions

Hgh-dose PPI triple therapy consisting of lansoprazole 60 mg bid, amoxicillin 1 g bid, and long-acting clarithromycin MR 1 g od for 7 days (n=55) or 14 days (n=55)

Outcomes

H.pylori eradication (same as above) and the relationship with CYP2C19 genotype and metronidazole resistance; adverse events

Notes


167

Wang 2013 Methods

Single centre RCT, no information regarding blinding

Participants

Country: China. 246 patients who were diagnosed as H. pylori infection (by RUT or UBT)

Interventions

Standard triple therapy consisted of esomeprazole 20 mg, amoxicillin 1000 mg and clarithromycin 500 mg for 7 days or 10 days; or concomitant therapy composed of esomeprazole 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg and tinidazole 500 mg bid for 7 days

Outcomes

H.pylori eradication 4 weeks after the end of the treatment by UBT

Notes

No raw data for ITT sample size in each group, need to contact authors

Xu 2012 Methods

Single centre, RCT

Participants

Country: China. 120 H. pylori-infected (by RUT together with culture or histology positive) patients with non-ulcer dyspepsia diagnosed by gastroscopy

Interventions

Quadruple therapy (omeprazole 20 mg bid, amoxicillin 1000 mg bid and clarithromycin 500 mg bid plus bismuth potassium citrate 220 mg bid) for 7 days or 14 days, or triple therapy omeprazole 20 mg bid, amoxicillin 1000 mg bid and clarithromycin 500 mg bid for 7 days

Outcomes

H. pylori eradication (by UBT) at least four weeks after the end of treatment, the relationship of eradication rate and the resistance rates of H. pylori to clarithromycin, metronidazole and amoxicillin; adverse events

Notes


168

DATA AND ANALYSES

Comparison 1. PPI + two antibiotics triple therapy, 14 days versus 7 days, main analyses

Outcome or subgroup title 1 H. pylori persistence, subgroup by antibiotics regimens, regardless of dose 1.1 PPI + clarithromycin+ amoxicillin 1.2 PPI+ clarithromycin+ a nitroimidazole 1.3 PPI+ amoxicillin+ a nitroimidazole 1.4 PPI+ amoxicillin+ a quinolone 2 Patients with adverse events, subgroup by antibiotics regimens, regardless of dose 2.1 PPI + clarithromycin+ amoxicillin 2.2 PPI+ clarithromycin+ a nitroimidazole 2.3 PPI+ amoxicillin+ a nitroimidazole 3 Patients discontinued treatment due to adverse events, subgroup by antibiotics regimens, regardless of dose 3.1 PPI + clarithromycin+ amoxicillin 3.2 PPI+ clarithromycin+ a nitroimidazole 3.3 PPI+ amoxicillin+ a nitroimidazole 3.4 PPI+ amoxicillin+ a quinolone

No. of studies

No. of participants

45

7722

Risk Ratio (M-H, Random, 95% CI)

0.66 [0.60, 0.74]

34

5801


0.65 [0.57, 0.75]

4

688


0.87 [0.71, 1.07]

10

1066


0.67 [0.52, 0.86]

2

167


0.37 [0.16, 0.83]

25

3971


1.20 [1.06, 1.37]

20

3225


1.21 [1.06, 1.39]

2

343


1.00 [0.67, 1.50]

4

403


1.73 [0.84, 3.58]

28

3990


1.14 [0.71, 1.82]

19

2705


1.15 [0.63, 2.10]

2

323


0.92 [0.35, 2.46]

8

795


1.95 [0.36, 10.65]

2

167


1.10 [0.16, 7.62]

Statistical method


Effect size

169


Outcome or subgroup title 1 H. pylori persistence, subgroup by antibiotics regimens, regardless of dose 1.1 PPI+ clarithromycin+ amoxicillin 1.2 PPI+ clarithromycin+ a nitroimidazole 1.3 PPI+ amoxicillin+ a nitroimidazole 1.4 PPI+ amoxicillin+ a quinolone 1.5 PPI+ amoxicillin+ a nitrofuran 2 Patients with adverse events, subgroup by antibiotics regimen, regardless of dose 2.1 PPI+ clarithromycin+ amoxicillin 2.2 PPI+ clarithromycin+ a nitroimidazole 2.3 PPI+ amoxicillin+ a nitroimidazole 2.4 PPI+ amoxicillin+ a quinolone 3 Patients discontinued treatment due to adverse events, subgroup by antibiotics regimen, regardless of dose 3.1 PPI+ clarithromycin+ amoxicillin 3.2 PPI+ clarithromycin+ a nitroimidazole 3.3 PPI+ amoxicillin+ a nitroimidazole 3.4 PPI+ amoxicillin+ a quinolone

No. of studies

No. of participants

24

4628


0.80 [0.72, 0.89]

17

3271


0.80 [0.70, 0.91]

2

148


0.99 [0.55, 1.79]

4

573


0.85 [0.65, 1.12]

2

346


0.58 [0.36, 0.95]

1

290


0.79 [0.52, 1.20]

11

2089


1.06 [0.87, 1.30]

8

1730


0.99 [0.79, 1.22]

1

99


1.48 [0.68, 3.18]

1

110


3.22 [0.13, 77.41]

1

150


1.64 [0.83, 3.22]

14

2284


1.18 [0.67, 2.06]

8

1335


1.01 [0.49, 2.09]

2

148


3.32 [0.36, 30.82]

3

455


1.45 [0.41, 5.18]

2

346


1.08 [0.23, 5.02]

Statistical method


Effect size

170


Outcome or subgroup title 1 H. pylori persistence, subgroup by antibiotics regimen, regardless of dose 1.1 PPI+ clarithromycin+ amoxicillin 1.2 PPI+ amoxicillin+ a nitroimidazole 2 Patients with adverse events, subgroup by antibiotics, regardless of dose 2.1 PPI+ clarithromycin+ amoxicillin 2.2 PPI+ amoxicillin+ a nitroimidazole 3 Patients discontinued treatment due to adverse events, subgroup by antibiotics regimens, regardless of dose 3.1 PPI+ clarithromycin+ amoxicillin 3.2 PPI+ amoxicillin+ a nitroimidazole

No. of studies

No. of participants

12

2111


0.72 [0.58, 0.90]

10

1596


0.69 [0.52, 0.91]

4

515


0.79 [0.54, 1.15]

5

789


1.01 [0.79, 1.29]

4

675


0.99 [0.77, 1.27]

1

114


4.34 [0.52, 36.02]

7

1215


0.94 [0.47, 1.89]

5

820


0.89 [0.36, 2.20]

3

395


1.02 [0.33, 3.15]

Statistical method

Effect size

Comparison 4. PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses

Outcome or subgroup title 1 H. pylori persistence, subgroup by regimens 1.1 PPI and clarithromycin and amoxicillin used twice daily at standard doses 1.2 PPI standard dose used once daily or low dose twice daily, clarithromycin and amoxicillin used twice daily at standard doses 1.3 PPI and amoxicillin standard dose used twice daily, clarithromycin used at low dose

No. of studies

No. of participants

34

5801


0.65 [0.57, 0.75]

28

5103


0.66 [0.59, 0.75]

3

198


0.80 [0.20, 3.29]

2

236


0.59 [0.32, 1.09]

Statistical method


Effect size

171

1.4 PPI used once daily, clarithromycin and amoxicillin both used at low dose 2 H. pylori persistence, subgroup by location 2.1 Asian countries 2.2 European countries 2.3 South or North American countries 2.4 South Africa 3 H. pylori persistence, subgroup by baseline PUD or FD 3.1 PUD patients 3.2 FD patients 3.3 Mixed PUD and FD, or without specifying the baseline disease 4 H. pylori persistence, subgroup by risk of bias: allocation concealment 4.1 Low risk 4.2 High risk 4.3 Unclear risk 5 H. pylori persistence, subgroup by risk of bias: overall 5.1 Low risk 5.2 High risk 5.3 Unclear risk 6 Patients with adverse events 7 Patients discontinuing treatment due to adverse events 8 Adverse events: Diarrhoea/ loose stool/increasing stool passage 9 Adverse event: Taste disturbance/metallic taste or glossitis 10 Adverse event: Nausea or vomiting 11 Adverse events: Skin rash and/or itching/allergic cutaneous reactions 12 Adverse event: Epigastric discomfort / Abdominal pain 13 Adverse event: Headache 14 Adverse event: Dry mouth/throat or thirsty 15 Adverse event: Stomatitis/Angular stomatitis 16 Adverse event: Loss of appetite 17 Adverse event: Tongue discolouration

3

264


0.52 [0.22, 1.24]

34

5801


0.65 [0.57, 0.75]

15 13 4

3167 2135 370

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

0.63 [0.52, 0.75] 0.66 [0.54, 0.82] 1.06 [0.51, 2.19]

2 34

129 5801

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

0.39 [0.15, 1.03] 0.66 [0.58, 0.75]

18 6 12

3823 411 1567


0.72 [0.63, 0.83] 0.70 [0.39, 1.26] 0.57 [0.44, 0.73]

34

5801


0.65 [0.57, 0.75]

3 2 29 34

1010 483 4308 5801

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

0.69 [0.37, 1.26] 0.50 [0.33, 0.74] 0.66 [0.57, 0.76] 0.65 [0.57, 0.75]

2 14 18 20 19

833 3081 1887 3225 2705

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

0.89 [0.68, 1.16] 0.68 [0.60, 0.79] 0.56 [0.42, 0.75] 1.21 [1.06, 1.39] 1.15 [0.63, 2.10]

11

2254


1.05 [0.76, 1.44]

8

1873


1.67 [1.10, 2.52]

8

2072


1.81 [1.10, 2.96]

7

1379


1.24 [0.46, 3.36]

5

1235


1.07 [0.55, 2.08]

3 2

911 709


1.73 [0.67, 4.44] 1.63 [0.32, 8.38]

2

709


1.47 [0.44, 4.91]

2 2

308 734


0.63 [0.12, 3.21] 0.45 [0.07, 3.03]


172

18 Adverse event: Dizziness 19 Adverse event: Regurgitation/belching 20 Adverse event: Bloating 21 Adverse event: Discolored faeces 22 Adverse event: Monilia 23 Adverse event: Herpes simplex labialis

2 2

324 201


0.97 [0.18, 5.23] 0.66 [0.08, 5.25]

2 1

201


1.08 [0.03, 36.21] Totals not selected


Totals not selected Totals not selected

1 1

Comparison 5. PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses

Outcome or subgroup title 1 H. pylori persistence, subgroup by regimen 1.1 PPI and clarithromycin and amoxicillin used twice daily and at standard doses 1.2 PPI used high dose twice daily, clarithromycin and amoxicillin used twice daily and at standard doses 1.3 PPI unclear dose twice daily, clarithromycin and amoxicillin used twice daily and at standard doses 2 H. pylori persistence, subgroup by location 2.1 Asian countries 2.2 European countries 2.3 South or North American 3 H. pylori persistence, subgroup by baseline PUD or FD 3.1 PUD patients 3.2 FD patients 3.3 Mixed PUD and FD, or without specifying the baseline disease 4 H. pylori persistence, subgroup by risk of bias: allocation concealment 4.1 Low risk 4.2 Unclear risk 4.3 High risk 5 H. pylori persistence, subgroup by risk of bias: overall 5.1 High risk

No. of studies

No. of participants

17

3271


0.80 [0.70, 0.91]

15

2919


0.79 [0.69, 0.91]

1

300


0.91 [0.59, 1.41]

1

52


0.66 [0.24, 1.82]

17

3271


0.80 [0.70, 0.91]

4 9 4 17

655 1958 658 3271


0.79 [0.57, 1.11] 0.78 [0.66, 0.92] 0.86 [0.65, 1.13] 0.79 [0.70, 0.90]

9 6 6

1672 755 844


0.87 [0.72, 1.05] 0.74 [0.57, 0.95] 0.73 [0.57, 0.94]

17

3271


0.80 [0.70, 0.91]

3 13 1 17

1098 1873 300 3271


0.84 [0.68, 1.04] 0.76 [0.64, 0.91] 0.91 [0.59, 1.41] 0.80 [0.70, 0.91]

8

1698


0.79 [0.66, 0.95]

Statistical method


Effect size

173

5.2 Unclear risk 6 Patients with adverse events 7 Patients discontinuing treatment due to adverse events 8 Adverse events: Taste disturbance or glossitis 9 Adverse event: Diarrhoea 10 Adverse event: Nausea or Vomiting 11 Adverse event: Abdominal pain 12 Adverse event: Skin rash or pruritus 13 Adverse event: Headache 14 Adverse event: Dyspepsia or worsened dyspepsia 15 Adverse event: Flatulence 16 Adverse event: Infection 17 Adverse event: Anorexia 18 Adverse event: Loss appetite 19 Adverse event: Erythaema 20 Adverse event: Candidiasis 21 Adverse event: Authors’ defined “serious adverse events“

9 8 8

1573 1730 1335


0.81 [0.67, 0.98] 0.99 [0.79, 1.22] 1.01 [0.49, 2.09]

5

1216


1.37 [0.86, 2.19]

5 4

1216 1030


0.92 [0.60, 1.42] 0.80 [0.42, 1.52]

3 3

862 585


1.41 [0.72, 2.74] 1.48 [0.26, 8.44]

2 2

631 579

Risk Ratio (M-H, Random, 95% CI) Odds Ratio (M-H, Random, 95% CI)

1.53 [0.77, 3.03] 0.51 [0.25, 1.05]

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected

1 1 1 1 1 1 1

Comparison 6. PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses

Outcome or subgroup title 1 H. pylori persistence, subgroup by regimen 1.1 PPI and two antibiotics used twice daily at standard doses 1.2 PPI type and dose not clear, antibiotics used twice daily at standard doses 2 H. pylori persistence, subgroup by location 2.1 Asian countries 2.2 European countries 2.3 North American countries 3 H. pylori persistence, subgroup by baseline PUD or FD 3.1 PUD patients 3.2 Mixed PUD and FD, or without specifying the baseline disease

No. of studies

No. of participants

10

1596


0.69 [0.52, 0.91]

9

1540


0.68 [0.50, 0.92]

1

56


0.74 [0.22, 2.49]

10

1596


0.69 [0.52, 0.91]

3 5 2 10

483 729 384 1596


0.46 [0.29, 0.74] 0.71 [0.45, 1.11] 0.93 [0.63, 1.37] 0.69 [0.52, 0.91]

5 5

950 646


0.73 [0.50, 1.09] 0.59 [0.38, 0.90]

Statistical method


Effect size

174

4 H. pylori persistence, subgroup by risk of bias: allocation concealment 4.1 Low risk 4.2 Unclear risk 5 H. pylori persistence, subgroup by risk of bias: overall 5.1 High risk 5.2 Unclear risk 6 Patients with adverse events 7 Patients discontinued treatment due to adverse events 8 Adverse event: Nausea/Vomiting 9 Adverse event: Diarrhoea 10 Adverse event: Taste disturbance or glossitis 11 Adverse event: Headache 12 Adverse event: Loss of appetite 13 Adverse event: Abdominal pain 14 Adverse event: Skin rash or itching

10

1596


0.69 [0.52, 0.91]

1 9 10

175 1421 1596


0.21 [0.05, 0.86] 0.73 [0.57, 0.94] 0.69 [0.52, 0.91]

3 7 4 5

444 1152 675 820


0.80 [0.49, 1.30] 0.62 [0.43, 0.90] 0.99 [0.77, 1.27] 0.89 [0.36, 2.20]

2 2 2

348 348 348


1.36 [0.52, 3.58] 0.87 [0.33, 2.25] 1.05 [0.45, 2.42]


Totals not selected Totals not selected Totals not selected Totals not selected

1 1 1 1

Comparison 7. PPI + clarithromycin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses

Outcome or subgroup title 1 H. pylori persistence, subgroup by regimen 1.1 PPI (lansoprazole or omeprazole) and two antibiotics used twice daily at standard doses 1.2 pantoprazole 40mg bid+clarithromycin 500mg bid+ metronidazole 500mg bid used only 10 days in the 14 days group 1.3 omeprazole 20mg bid+ clarithromycin 250mg bid + metronidazole 250mg qid 2 H. pyloris persistence, subgroup by location 2.1 Eruopean countries 3 H. pyloris persistence, subgroup by baseline PUD or FD 3.1 PUD patients 3.2 FD patients

No. of studies

No. of participants

4

688


0.87 [0.71, 1.07]

2

345


0.85 [0.66, 1.12]

1

244


0.95 [0.62, 1.46]

1

99


0.76 [0.38, 1.53]

4

688


0.87 [0.71, 1.07]

4 4

688 688


0.87 [0.71, 1.07] 0.87 [0.71, 1.07]

1 2

244 201


0.95 [0.62, 1.46] 0.69 [0.42, 1.11]

Statistical method


Effect size

175

3.3 Mixed PUD and FD patients 4 H. pyloris persistence, subgroup by risk of bias: overall 4.1 Unclear risk 4.2 High risk 5 Patients with adverse events 6 Patients discontinuing treatment due to adverse events

1

243


0.91 [0.69, 1.19]

4

688


0.87 [0.71, 1.07]

1 3 2 2

102 586 343 323


0.63 [0.32, 1.22] 0.90 [0.73, 1.12] 1.00 [0.67, 1.50] 0.92 [0.35, 2.46]

Comparison 8. PPI + clarithromycin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses

Outcome or subgroup title 1 H. pylori persistence, subgroup by regimen 1.1 Rabeprazole 20mg bid +clarithromycin 500mg bid + tinidazole 500mg bid 1.2 Omeprazole 20mg bid+ clarithromycin 250mg bid+ metronidazole 400mg bid 2 Patients with adverse events 3 Patients discontined treatment due to adverse events

Comparison 9. analyses

No. of studies

No. of participants

2

148


0.99 [0.55, 1.79]

1

99


1.03 [0.56, 1.90]

1

49


0.52 [0.05, 5.38]

1 2

99 148


1.48 [0.68, 3.18] 3.32 [0.36, 30.82]

Statistical method

Effect size

PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE

Outcome or subgroup title 1 H. pylori persistence, subgroup by regimen 1.1 PPI, amoxicillin used twice daily at standard doses, metronidazole 400mg bid 1.2 PPI, amoxicillin used twice daily at standard doses, metronidazole 500mg bid 1.3 PPI, amoxicillin used twice daily at standard doses, metronidazole 250mg qid

No. of studies

No. of participants

10

1066


0.67 [0.53, 0.85]

4

346


0.64 [0.41, 1.01]

4

561


0.64 [0.40, 1.01]

1

64


1.13 [0.48, 2.67]

Statistical method


Effect size

176

1.4 PPI, amoxicillin used twice daily at standard doses, tinidazole 500mg bid 2 H. pylori persistence subgroup by location 2.1 European countries 2.2 Asian countries 3 H. pylori persistence, subgroup by baseline PUD or FD 3.1 PUD patients 3.2 FD patients 3.3 Mixed PUD and FD, or without specifying the baseline disease 4 H. pylori persistence subgroup by risk of bias: allocation concealment 4.1 Low risk 4.2 Unclear risk 5 H. pylori persistence subgroup by risk of bias: overall 5.1 High risk 5.2 Unclear risk 6 Patients with adverse events 7 Patients discontinuing treatment due to adverse events 8 Adverse events: Diarrhoea 9 Adverse event: Nausea/vomiting/epigastric discomfort 10 Adverse events: Metallic taste/dysgeusia/taste disturbance 11 Adverse event: Epigastric pain/abdominal pain 12 Adverse event: Dizziness 13 Adverse events: Skin rush 14 Adverse event: Headache 15 Adverse event: Flatulence 16 Adverse event: Malaise 17 Adverse event: Heartburn 18 Advere event: Regurgitation 19 Adverse event: Pruritus 20 Adverse event: Loss of appetite

2

95


0.57 [0.26, 1.27]

10

1066


0.67 [0.52, 0.86]

4 6 10

526 540 1066


0.68 [0.41, 1.13] 0.63 [0.45, 0.89] 0.67 [0.52, 0.86]

5 1 4

434 147 485


0.67 [0.47, 0.94] 0.85 [0.38, 1.93] 0.63 [0.38, 1.04]

10

1066


0.67 [0.52, 0.86]

2 8 10

298 768 1066


0.54 [0.14, 2.11] 0.67 [0.51, 0.87] 0.67 [0.52, 0.86]

6 4 4 8

523 543 403 795


0.81 [0.58, 1.12] 0.54 [0.37, 0.78] 1.73 [0.84, 3.58] 1.95 [0.36, 10.65]

4 3

492 379


0.98 [0.31, 3.16] 1.12 [0.46, 2.74]

3

339


1.58 [0.67, 3.71]

2

333


1.19 [0.41, 3.48]

2 2 2 1 1 1 1 1 1

199 87 298

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

1.80 [0.24, 13.59] 0.94 [0.10, 8.70] 1.23 [0.50, 3.05] Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected


177

Comparison 10. PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses

Outcome or subgroup title 1 H. pylori persistence, subgroup by regimen 1.1 PPI, amoxicillin twice daily at standard doses, metronidazole 500mg bid 1.2 PPI, amoxicillin twice daily at standard doses, metronidazole 250mg qid 1.3 PPI, amoxicillin twice daily at standard doses, tinidazole 500mg bid 2 H. pylori persistence subgroup by location 2.1 European countries 3 H. pylori persistence subgroup by baseline PUD or FD 3.1 PUD patients 3.2 Mixed PUD and FD, or without specifying the baseline disease 4 H. pylori persistence, subgroup by risk of bias: allocation concealment 4.1 Low risk 4.2 Unclear risk 5 H. pylori persistence, subgroup by risk of bias: overall 5.1 High risk 5.2 Unclear risk 6 Patients with adverse events 7 Patients discontinuing treatment due to adverse events 8 Adverse event: Nausea/Vomiting 9 Adverse event: Diarrhoea 10 Adverse event: Abdominal pain 11 Adverse event: Loss of appetite 12 Adverse event: Headache 13 Adverse event: Taste disturbance

No. of studies

No. of participants

4

573


0.85 [0.65, 1.12]

3

463


0.82 [0.61, 1.11]

1

57


1.11 [0.45, 2.76]

1

53


0.89 [0.34, 2.30]

4

573


0.85 [0.65, 1.12]

4 4

573 573


0.85 [0.65, 1.12] 0.85 [0.65, 1.12]

1 3

106 467


1.07 [0.58, 1.99] 0.81 [0.60, 1.09]

4

573


0.85 [0.65, 1.12]

2 2 4

349 224 573


0.85 [0.58, 1.24] 0.86 [0.58, 1.25] 0.85 [0.65, 1.12]

2 2 1 3

216 357 110 455


1.04 [0.66, 1.63] 0.76 [0.55, 1.07] 3.22 [0.13, 77.41] 1.45 [0.41, 5.18]

2 1 1 1 1 1

349

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

1.22 [0.55, 2.70] Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected

Statistical method


Effect size

178

Comparison 11. PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses

Outcome or subgroup title 1 H. pylori persistence, subgroup by regimen 1.1 PPI and amoxicillin used twice daily at standard doses, metronidazole 500mg bid 1.2 PPI and amoxicillin used twice daily at standard doses, metronidazole 250mg qid 1.3 PPI and amoxicillin used twice daily at standard doses, tinidazole 500mg bid 2 H. pylori persistence subgroup by location 2.1 European countries 3 H. pylori persistence, subgroup by baseline PUD or FD 3.1 PUD patients 3.2 Mixed PUD and FD, or without specifying the baseline disease 4 H. pylori persistence, subgroup by risk of bias: allocation concealment 4.1 Low risk 4.2 Unclear risk 5 H. pylori persistence, subgroup by risk of bias: overall 5.1 High risk 5.2 Unclear risk 6 Patients with adverse events 7 Patients discontinuing treatment due to adverse event 8 Adverse event: Diarrhoea 9 Adverse event: Dysgeusia/taste disturbance 10 Adverse event: Nausea/Vomiting 11 Adverse event: Headache 12 Adverse event: Loss of appetite 13 Adverse event: Abdominal pain

No. of studies

No. of participants

4

515


0.80 [0.57, 1.12]

3

401


0.71 [0.43, 1.17]

1

61


1.02 [0.44, 2.39]

1

53


0.96 [0.36, 2.61]

4

515


0.79 [0.54, 1.15]

4 4

515 515


0.79 [0.54, 1.15] 0.79 [0.54, 1.15]

1 3

106 409


0.93 [0.50, 1.74] 0.72 [0.42, 1.23]

4

515


0.79 [0.54, 1.15]

2 2 4

289 226 515


0.62 [0.21, 1.86] 0.85 [0.55, 1.30] 0.79 [0.54, 1.15]

2 2 1 3

220 295 114 395


0.97 [0.62, 1.51] 0.57 [0.25, 1.29] 4.34 [0.52, 36.02] 1.02 [0.33, 3.15]

2 2

289 289


1.42 [0.33, 6.12] 1.68 [0.65, 4.39]

2

289


0.66 [0.23, 1.88]

2 1 1

289


1.09 [0.45, 2.65] Totals not selected Totals not selected

Statistical method


Effect size

179

Comparison 12. PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses

Outcome or subgroup title 1 H. pylori persistence, subgroup by regimens 1.1 Rabeprazole 20mg bid+amoxicillin 1g bid+ofloxacin 400mg bid 1.2 Lansoprazole 30 mg bid + amoxicillin 1g bid + levofloxacin 500mg od 2 H. pylori persistence: subgroup by location 2.1 Asian countries 2.2 North Americian countries 3 H. pylori persistence: subgroup by baseline PUD or FD 3.1 FD patients 3.2 Mixed PUD and FD patients 4 Patients discontinuing treatment due to adverse events 5 Adverse events: Diarrhoea 6 Adverse events: Headache 7 Adverse events: Skin rush or pruritus 8 Adverse event: nausea/vomiting 9 Adverse event: Allergic reaction

No. of studies

No. of participants

2

167


0.37 [0.16, 0.83]

1

76


0.20 [0.06, 0.65]

1

91


0.48 [0.31, 0.76]

2

167


0.37 [0.16, 0.83]

1 1

91 76


0.48 [0.31, 0.76] 0.20 [0.06, 0.65]

2

167


0.37 [0.16, 0.83]

1 1

91 76


0.48 [0.31, 0.76] 0.20 [0.06, 0.65]

2

167


1.10 [0.16, 7.62]

1 1 1


Totals not selected Totals not selected Totals not selected

1 1



Statistical method

Effect size

Comparison 13. PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses

Outcome or subgroup title 1 H. pylori persistence, subgroup by regimens 1.1 Lansoprazole 30mg bid + amoxicillin 1g bid+ moxifloxacin 200mg bid 1.2 Esomeprazole 20mg bid+ amoxicillin1g bid+ moxifloxacin 400mg bid 2 H. pylori persistence subgroup by location 2.1 European countries

No. of studies

No. of participants

2

346


0.58 [0.36, 0.95]

1

150


0.67 [0.35, 1.29]

1

196


0.49 [0.23, 1.02]

2

346


0.58 [0.36, 0.95]

2

346


0.58 [0.36, 0.95]

Statistical method


Effect size

180

3 H. pylori persistence subgroup by baseline PUD or FD 3.1 FD patients 3.2 Mixed PUD and FD patients 4 Patients with adverse events 5 Patients discontinuing treatment due to adverse events 6 Adverse event: Epigastric discomfort/abdominal pain 7 Adverse event: Nausea or vomiting 8 Adverse event: Diarrrhoea 9 Adverse event: Metallic taste/taste disturbances 10 Adverse event: Constipation 11 Adverse event: Headache 12 Adverse event: Pruritus 13 Adverse event: Skin rash 14 Adverse event: Aphthous stomatitis 15 Adverse event: Bloating 16 Adverse event: loose stools

2

346


0.58 [0.36, 0.95]

1 1

150 196


0.67 [0.35, 1.29] 0.49 [0.23, 1.02]

1 2

150 346


1.64 [0.83, 3.22] 1.08 [0.23, 5.02]

2

337


1.27 [0.35, 4.63]

2

337


1.22 [0.42, 3.57]

2 2

337 337


1.44 [0.46, 4.46] 1.41 [0.11, 18.68]

1 1 1 1 1


Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected

1 1



Comparison 14. PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days

Outcome or subgroup title 1 H. pylori persistence, subgroup by regimen 1.1 Omeprazole 20mg bid+ bismuth 240mg bid + tetracycline 750mg bid + metronidazole 500mg bid 1.2 Omeprazole 20mg bid + bismuth substrate 240mg bid + furazolidone 200mg bid+ amoxicillin 1g bid 1.3 Omeprazole 20mg bid +bismuth potassium citrate 220mg bid+ clarithromycin 500mg bid+ amoxicillin 1g bid 2 H. pylori persistence, subgroup by location 2.1 Asian countries 3 H. pylori persistence, subgroup by baseline PUD or FD 3.1 FD patients

No. of studies

No. of participants

3

362


0.71 [0.44, 1.15]

1

46


0.78 [0.53, 1.15]

1

156


0.95 [0.57, 1.59]

1

160


0.31 [0.12, 0.81]

3

362


0.71 [0.44, 1.15]

3 3

362 362


0.71 [0.44, 1.15] 0.71 [0.44, 1.15]

1

160


0.31 [0.12, 0.81]

Statistical method


Effect size

181

3.2 Mixed PUD or FD patients 4 H. pylori persistence, subgroup by risk of bias: overall 4.1 High risk 4.2 Unclear risk 5 Patients with adverse events 6 Patients discontinuing treatment due to adverse events 7 Adverse event: Diarrhoea 8 Adverse event: Skin rash/itching 9 Adverse event: Dizziness/drowsiness 10 Adverse event: Abdominal discomfort 11 Adverse event: Fever 12 Adverse event: Vomiting 13 Adverse event: Fatigue 14 Adverse event: Headache 15 Adverse event: Nausea

2

202


0.84 [0.62, 1.15]

3

362


0.71 [0.44, 1.15]

1 2 2 2

160 202 316 316


0.31 [0.12, 0.81] 0.84 [0.62, 1.15] 1.13 [0.67, 1.92] 7.48 [1.38, 40.63]

2 2 2

316 316 316


1.38 [0.54, 3.56] 0.43 [0.06, 2.91] 1.12 [0.44, 2.84]

1


Totals not selected

1 1 1 1 1


Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected


Outcome or subgroup title 1 H. pylori persistence, subgroup by regimens 1.1 Pantoprazole 40mgbid+ colloidal bismuth subcitrate 220mgbid + metronidazole 400mgtid + tetracycline 750mgbid 1.2 Rabeprazole 10mg bid+ bismuth 220mb bid+ amoxicillin 1g bid+ furazolidone 100mg bid 2 H. pylori persistence, subgroup by location 2.1 Asian countries 3 H. pylori persistence, subgroup by baseline disease 3.1 FD patients 3.2 PUD patients 4 Patients discontinuing treatment due to adverse events

No. of studies

No. of participants

2

378


0.70 [0.43, 1.14]

1

88


0.53 [0.19, 1.46]

1

290


0.76 [0.44, 1.32]

2

378


0.70 [0.43, 1.14]

2 2

378 378


0.70 [0.43, 1.14] 0.70 [0.43, 1.14]

1 1 1

88 290 88


0.53 [0.19, 1.46] 0.76 [0.44, 1.32] 0.96 [0.06, 14.80]

Statistical method


Effect size

182


Outcome or subgroup title 1 H. pylori persistence 1.1 PPI+ bismuth subcitrate 240mg + metronidazole 500mg + tetracycline 500mg BID 2 Patients with adverse events 3 Patients discontinuing treatment due to adverse events 4 Adverse events: nausea 5 Adverse events: vomiting 6 Adverse events: Stomach ache 7 Adverse events: diarrhoea 8 Adverse events: glossitis 9 Adverse events: vaginitis 10 Adverse events: dysphagia 11 Adverse events: dizziness 12 Adverse events: unfitness/discomfort (patients reported) 13 Adverse events: fatigue/weakness (patients reported)

No. of studies

No. of participants

1 1

417 417


1.13 [0.59, 2.18] 1.13 [0.59, 2.18]

1 1

417 417


1.55 [0.93, 2.57] 1.42 [0.32, 6.26]

1 1 1 1 1 1 1 1 1

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected

1


Totals not selected

Statistical method

Effect size

Comparison 17. PPI + three antibiotics quadruple therapy, 10 days versus 7 days

Outcome or subgroup title 1 H. pylori persistence 1.1 Omeprazole+ levofloxacin+ nitazoxanide+ doxycycline 2 Patients discontinuing treatment due to adverse events 2.1 Omeprazole+ levofloxacin+ nitazoxanide+ doxycycline

No. of studies

No. of participants

1 1

180 180


1.11 [0.47, 2.60] 1.11 [0.47, 2.60]

1

180


1.67 [0.41, 6.77]

1

180


1.67 [0.41, 6.77]

Statistical method


Effect size

183

Comparison 18. PPI dual therapy (PPI + one antibiotic) 14 days versus 7 days

Outcome or subgroup title 1 H. pylori persistence 1.1 High dose PPI (omeprazole 60mg bid)+ Clarithromycin 500mg bid 2 Patients with adverse events

No. of studies

No. of participants

1 1

64 64


1.18 [0.56, 2.52] 1.18 [0.56, 2.52]

1

64


3.55 [1.08, 11.70]

Statistical method

Effect size

Comparison 19. PPI dual therapy (PPI + one antibiotic), 10 days versus 7 days

Outcome or subgroup title 1 H. pylori persistence 1.1 Rabeprazole 20mg od + levofloxacin 500mg od 2 Patients with adverse events 3 Patients discontinuing treatment due to adverse events

No. of studies

No. of participants

1 1

80 80


1.17 [0.62, 2.20] 1.17 [0.62, 2.20]

1 1

80 80


13.0 [0.76, 223.33] 0.0 [0.0, 0.0]

Statistical method

Effect size

Comparison 20. H2 RA bismuth quadruple therapy, 14 days versus 7 days

Outcome or subgroup title 1 H. pylori persistence 1.1 Ranitidine 300mg bid, CBS 240mg bid, amoxicillin 1g bid, metronidazole 500mg bid 2 Patients discontinuing treatment due to adverse events 3 Adverse event: Anorexia 4 Adverse event: Nausea 5 Adverse event: Vomiting 6 Adverse event: Diarrhoea 7 Adverse event: Constipation 8 Adverse event; Dizziness 9 Adverse event: Headache 10 Adverse event: Fatigue 11 Adverse event: Unpleasant taste 12 Adverse event: Dry mouth 13 Adverse event: Anal itching 14 Adverse event: Dysuria

No. of studies

No. of participants

1 1

160 160


0.49 [0.36, 0.67] 0.49 [0.36, 0.67]

1

160


3.00 [0.12, 72.56]

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected

1 1 1 1 1 1 1 1 1 1 1 1

Statistical method


Effect size

184

15 Adverse event: Urticaria

1


Totals not selected

Comparison 21. H2 RA bismuth quadruple therapy, 10 days versus 7 days

Outcome or subgroup title 1 H. pylori persistence, subgroup by regimen 1.1 RBC 400mg bid + metronidazole 500mg bid+ tetracycline 500mg bid 1.2 RBC 400mg bid+ metronidazole 500mg bid+ clarithromycin 250mg bid 2 Patients with adverse event 3 Patients discontinuing treatment due to adverse events 4 Adverse event: Epigastric pain 5 Adverse event: Nausea 6 Adverse event: Diarrhoea 7 Adverse event: Vomiting 8 Adverse event: Headache 9 Adverse event: Skin rash 10 Adverse event: Taste disturbance

No. of studies

No. of participants

2

215


0.88 [0.59, 1.32]

1

105


0.88 [0.56, 1.39]

1

110


0.89 [0.37, 2.13]

2 1

215 110


1.07 [0.78, 1.46] 3.00 [0.32, 27.96]

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected

1 1 1 1 1 1 1

Statistical method

Effect size

Comparison 22. H2 RA bismuth-based triple therapy, 14 days versus 7 days

Outcome or subgroup title 1 H. pylori persistence 1.1 RBC 400mg bid and clarithromycin 500mg bid 2 Patients with adverse events 3 Patients discontinuing treatment due to adverse events 4 Adverse event: Nausea 5 Adverse event: Headache 6 Adverse event: Pruritus 7 Adverse event: Allergic dermatitis 8 Adverse event: Conjunctivitis 9 Adverse event: Asthenia

No. of studies

No. of participants

2 2

232 232


0.84 [0.53, 1.33] 0.84 [0.53, 1.33]

2 2

221 221


0.68 [0.23, 2.02] 0.33 [0.01, 8.01]

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected Totals not selected

1 1 1 1 1 1

Statistical method


Effect size

185

Comparison 23. H2 RA triple therapy (H2 RA + two antibiotics), 14 days versus 7 days

Outcome or subgroup title 1 H. pylori persistence, subgroup by regimen 1.1 Famotidine 20mg bid, amoxicillin 1g bid, metronidazole 400mg bid 1.2 Famotidine 40mg bid, amoxicillin 1g bid, tinidazole 500mg bid 1.3 Lufatidine 20mg bid, clarithromycin 500mg bid, amoxicillin 1g bid 2 H. pylori persistence, subgroup by location 2.1 Asian countries 3 H. pylori persistence, subgroup by baseline PUD or FD 3.1 PUD patients 3.2 Mixed PUD and FD or gastritis patients 4 H. pylori persistence, subgroup by risk of bias: allocation concealment 4.1 low risk of bias 4.2 Unclear risk of bias 5 H. pylori persistence, subgroup by risk of bias: overall 5.1 low risk of bias 5.2 High risk of bias 6 Patients with adverse events 7 Patients discontinuing treatment due to adverse events 8 Adverse event: Diarrhoea 9 Adverse event: Nausea or Vomiting 10 Adverse event: Headache 11 Adverse event: Taste alteration 12 Adverse event: Epigastric discomfort 13 Adverse event: Dizziness

No. of studies

No. of participants

3

417


0.64 [0.40, 1.03]

1

63


0.42 [0.19, 0.93]

1

120


0.55 [0.30, 1.00]

1

234


0.93 [0.58, 1.49]

3

417


0.64 [0.40, 1.03]

3 3

417 417


0.64 [0.40, 1.03] 0.64 [0.40, 1.03]

1 2

234 183


0.93 [0.58, 1.49] 0.50 [0.31, 0.80]

3

417


0.64 [0.40, 1.03]

1 2 3

234 183 417


0.93 [0.58, 1.49] 0.50 [0.31, 0.80] 0.64 [0.40, 1.03]

1 2 2 3

234 183 354 417


0.93 [0.58, 1.49] 0.50 [0.31, 0.80] 1.32 [0.72, 2.41] 0.32 [0.01, 7.83]

2 2

354 354


1.74 [0.81, 3.71] 2.85 [0.91, 8.90]

1 1 1


Totals not selected Totals not selected Totals not selected

1


Totals not selected

Statistical method


Effect size

186

Comparison 24. Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days

Outcome or subgroup title 1 H. pylori persistence, subgroup by regimen 1.1 Bismuth Subsalicylate 250mg bid, tetracycline 500mg bid, metronidazole 250mg bid 1.2 CBS 120mg qid, tetracycline 500mg qid, metronidazole 500mg bid 2 Patients with adverse events 3 Patients discontinuing treatment due to adverse events 4 Adverse event: Nausea 5 Adverse event: Vomiting 6 Adverse event: Metalic taste or bad taste 7 Adverse event: Heartburn 8 Adverse event: Diarrhoea 9 Adverse event: Stomach pain 10 Adverse event: Burning sensation in the oesophagus 11 Adverse event: Burning sensation in the mouth 12 Adverse event: Dysphagia 13 Adverse event: Burping 14 Adverse event: Anorexia 15 Adverse event: Dizziness

No. of studies

No. of participants

2

153


0.76 [0.37, 1.54]

1

42


0.67 [0.29, 1.54]

1

111


1.06 [0.28, 4.01]

2 2

151 151


1.10 [0.93, 1.29] 2.86 [0.71, 11.51]

2 2 2

151 151 151


1.26 [0.86, 1.86] 2.11 [0.71, 6.27] 1.00 [0.71, 1.40]

1 1 1 1



1


Totals not selected

1 1 1 1

Risk Ratio (M-H, Random, 95% CI) Odds Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)


Statistical method


Effect size

187

Analysis 1.1. Comparison 1 PPI + two antibiotics triple therapy, 14 days versus 7 days, main analyses, Outcome 1 H. pylori persistence, subgroup by antibiotics regimens, regardless of dose. Review:

Optimum duration of regimens for Helicobacter

pylori eradication

Comparison: 1 PPI + two antibiotics triple therapy, 14 days versus 7 days, main analyses Outcome: 1 H.

pylori persistence, subgroup by antibiotics regimens, regardless of dose

Study or subgroup

Favours 14 days

7 days

Risk Ratio MH,Random,95% CI

Weight


n/N

n/N

Laine 1996

4/50

7/50

0.8 %

0.57 [ 0.18, 1.83 ]

Moayyedi 1996

6/38

5/35

0.9 %

1.11 [ 0.37, 3.30 ]

Mones 1997

4/61

5/65

0.7 %

0.85 [ 0.24, 3.03 ]

Katicic 1997

9/52

15/55

1.7 %

0.63 [ 0.30, 1.32 ]

Louw 1998a

2/30

6/32

0.5 %

0.36 [ 0.08, 1.63 ]

Louw 1998b

3/34

7/33

0.7 %

0.42 [ 0.12, 1.47 ]

Paoluzi 1998

6/53

16/54

1.3 %

0.38 [ 0.16, 0.90 ]

10/55

22/86

2.0 %

0.71 [ 0.36, 1.38 ]

Simsek 1999

5/26

6/25

0.9 %

0.80 [ 0.28, 2.29 ]

Kiyota 1999

8/69

17/78

1.6 %

0.53 [ 0.24, 1.16 ]

Nakagawa 1999

10/46

14/60

1.8 %

0.93 [ 0.46, 1.90 ]

Yang 1999

11/57

20/55

2.1 %

0.53 [ 0.28, 1.00 ]

Kang 2000a

12/138

32/133

2.2 %

0.36 [ 0.19, 0.67 ]

Bhasin 2000

1/24

10/22

0.3 %

0.09 [ 0.01, 0.66 ]

Cho 2001

7/87

21/82

1.5 %

0.31 [ 0.14, 0.70 ]

Antelo 2001

5/40

4/40

0.7 %

1.25 [ 0.36, 4.32 ]

Maconi 2001

10/71

18/71

1.9 %

0.56 [ 0.28, 1.12 ]

Palmas 2002

18/64

21/66

2.8 %

0.88 [ 0.52, 1.50 ]

Gumurdulu 2004

35/59

40/53

5.5 %

0.79 [ 0.61, 1.02 ]

Lee 2004

34/342

51/328

3.8 %

0.64 [ 0.43, 0.96 ]

Hu 2004

10/83

15/87

1.7 %

0.70 [ 0.33, 1.47 ]

Keum 2005

23/211

35/141

3.1 %

0.44 [ 0.27, 0.71 ]

Paoluzi 2006

38/126

50/117

4.5 %

0.71 [ 0.50, 0.99 ]

1 PPI + clarithromycin+ amoxicillin

Mantzaris 1999

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days

(Continued . . . )


188

(. . . Study or subgroup

Favours 14 days

7 days


Weight

Continued) Risk Ratio MH,Random,95% CI

n/N

n/N

Aydin 2007

15/40

24/40

3.2 %

0.63 [ 0.39, 1.00 ]

Garza Gonz lez 2007

11/29

4/30

1.0 %

2.84 [ 1.02, 7.92 ]

9/62

15/69

1.7 %

0.67 [ 0.31, 1.42 ]

Zagari 2007

56/302

62/302

4.7 %

0.90 [ 0.65, 1.25 ]

Kim 2007

64/261

97/337

5.3 %

0.85 [ 0.65, 1.12 ]

Scaccianoce 2008

5/17

7/15

1.2 %

0.63 [ 0.25, 1.57 ]

Suriani 2008

2/23

7/26

0.5 %

0.32 [ 0.07, 1.40 ]

22/112

27/117

3.0 %

0.85 [ 0.52, 1.40 ]

Park 2009a

4/29

7/25

0.9 %

0.49 [ 0.16, 1.49 ]


2/57

28/120

0.6 %

0.15 [ 0.04, 0.61 ]

10/102

26/102

2.0 %

0.38 [ 0.20, 0.76 ]

2850

2951

66.9 %

0.65 [ 0.57, 0.75 ]

Riquelme 2007

Kim 2008

Karatapanis 2011

Subtotal (95% CI)

Total events: 471 (Favours 14 days), 741 (7 days) Heterogeneity: Tau2 = 0.04; Chi2 = 47.38, df = 33 (P = 0.05); I2 =30% Test for overall effect: Z = 6.22 (P < 0.00001) 2 PPI+ clarithromycin+ a nitroimidazole Dal Bo’ 1998

8/33

21/66

1.9 %

0.76 [ 0.38, 1.53 ]

Paoluzi 1998

10/48

18/54

2.0 %

0.63 [ 0.32, 1.22 ]

Dammann 2000

31/123

32/121

3.6 %

0.95 [ 0.62, 1.46 ]

Paoluzi 2006

53/121

59/122

5.3 %

0.91 [ 0.69, 1.19 ]

325

363

12.8 %

0.87 [ 0.71, 1.07 ]

Subtotal (95% CI)

Total events: 102 (Favours 14 days), 130 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 1.35, df = 3 (P = 0.72); I2 =0.0% Test for overall effect: Z = 1.30 (P = 0.19) 3 PPI+ amoxicillin+ a nitroimidazole Katicic 1997

15/62

25/60

2.7 %

0.58 [ 0.34, 0.99 ]

4/25

6/21

0.8 %

0.56 [ 0.18, 1.72 ]

Wong 2000

14/82

16/71

2.1 %

0.76 [ 0.40, 1.44 ]

Pellicano 2002

14/53

14/53

2.1 %

1.00 [ 0.53, 1.89 ]

Cui 2002

9/72

11/75

1.4 %

0.85 [ 0.38, 1.93 ]

Hu 2003

7/39

6/26

1.1 %

0.78 [ 0.29, 2.05 ]

Chaudhary 2004

4/20

11/21

1.1 %

0.38 [ 0.15, 1.00 ]

Hu 2004

7/44

15/44

1.5 %

0.47 [ 0.21, 1.03 ]

15/61

14/57

2.2 %

1.00 [ 0.53, 1.88 ]

Hu 1999

Berrutti 2008

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days

(Continued . . . ) Optimum duration of regimens for Helicobacter pylori eradication (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

189

(. . . 7 days


Weight


Study or subgroup

Favours 14 days n/N

n/N


4/58

32/122

1.0 %

0.26 [ 0.10, 0.71 ]

Subtotal (95% CI)

516

550

16.2 %

0.67 [ 0.52, 0.86 ]

Total events: 93 (Favours 14 days), 150 (7 days) Heterogeneity: Tau2 = 0.01; Chi2 = 9.66, df = 9 (P = 0.38); I2 =7% Test for overall effect: Z = 3.20 (P = 0.0014) 4 PPI+ amoxicillin+ a quinolone Bosques-Padilla 2004 Ercin 2010

3/39

14/37

0.8 %

0.20 [ 0.06, 0.65 ]

14/40

37/51

3.3 %

0.48 [ 0.31, 0.76 ]

79

88

4.1 %

0.37 [ 0.16, 0.83 ]

100.0 %

0.66 [ 0.60, 0.74 ]

Subtotal (95% CI) Total events: 17 (Favours 14 days), 51 (7 days)

Heterogeneity: Tau2 = 0.20; Chi2 = 1.98, df = 1 (P = 0.16); I2 =49% Test for overall effect: Z = 2.40 (P = 0.016)

Total (95% CI)

3770

3952

Total events: 683 (Favours 14 days), 1072 (7 days) Heterogeneity: Tau2 = 0.04; Chi2 = 70.06, df = 49 (P = 0.03); I2 =30% Test for overall effect: Z = 7.36 (P < 0.00001) Test for subgroup differences: Chi2 = 7.80, df = 3 (P = 0.05), I2 =62%

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


190

Analysis 1.2. Comparison 1 PPI + two antibiotics triple therapy, 14 days versus 7 days, main analyses, Outcome 2 Patients with adverse events, subgroup by antibiotics regimens, regardless of dose. Review:


pylori eradication

Comparison: 1 PPI + two antibiotics triple therapy, 14 days versus 7 days, main analyses Outcome: 2 Patients with adverse events, subgroup by antibiotics regimens, regardless of dose

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Laine 1996

14/50

15/50

4.2 %

0.93 [ 0.51, 1.72 ]

Moayyedi 1996

31/37

18/33

13.7 %

1.54 [ 1.09, 2.16 ]

Mones 1997

9/61

7/65

1.9 %

1.37 [ 0.54, 3.45 ]

Louw 1998b

6/34

7/33

1.7 %

0.83 [ 0.31, 2.22 ]

Louw 1998a

8/30

7/32

2.0 %

1.22 [ 0.50, 2.95 ]

Yang 1999

9/50

8/45

2.1 %

1.01 [ 0.43, 2.40 ]

Kiyota 1999

23/65

16/74

5.4 %

1.64 [ 0.95, 2.82 ]

Mantzaris 1999

6/49

8/77

1.6 %

1.18 [ 0.44, 3.19 ]

Bhasin 2000

1/24

1/22

0.2 %

0.92 [ 0.06, 13.79 ]

Cho 2001

20/87

13/82

4.0 %

1.45 [ 0.77, 2.72 ]

Maconi 2001

14/71

14/71

3.6 %

1.00 [ 0.51, 1.94 ]

Antelo 2001

18/39

19/39

7.3 %

0.95 [ 0.59, 1.51 ]

5/80

3/62

0.8 %

1.29 [ 0.32, 5.20 ]

Riquelme 2007

23/62

20/69

6.6 %

1.28 [ 0.78, 2.09 ]

Aydin 2007

13/34

12/34

4.1 %

1.08 [ 0.58, 2.02 ]

Kim 2007

12/261

17/337

3.1 %

0.91 [ 0.44, 1.87 ]

Zagari 2007

30/302

29/301

6.8 %

1.03 [ 0.63, 1.67 ]

Kim 2008

24/112

18/117

5.2 %

1.39 [ 0.80, 2.42 ]

Scaccianoce 2008

5/15

3/15

1.0 %

1.67 [ 0.48, 5.76 ]

Karatapanis 2011

36/102

30/102

10.0 %

1.20 [ 0.80, 1.79 ]

1565

1660

85.6 %

1.21 [ 1.06, 1.39 ]


Hu 2004

Subtotal (95% CI)

Total events: 307 (14 days), 265 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 8.03, df = 19 (P = 0.99); I2 =0.0% Test for overall effect: Z = 2.76 (P = 0.0058) 2 PPI+ clarithromycin+ a nitroimidazole

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days

(Continued . . . )


191


14 days


Weight


n/N

n/N

3/33

5/66

0.9 %

1.20 [ 0.31, 4.72 ]

32/123

32/121

9.0 %

0.98 [ 0.65, 1.50 ]

156

187

9.9 %

1.00 [ 0.67, 1.50 ]

Dal Bo’ 1998 Dammann 2000

7 days

Subtotal (95% CI) Total events: 35 (14 days), 37 (7 days)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.07, df = 1 (P = 0.79); I2 =0.0% Test for overall effect: Z = 0.00 (P = 1.0) 3 PPI+ amoxicillin+ a nitroimidazole 9/25

2/21

0.8 %

3.78 [ 0.92, 15.61 ]

11/82

8/71

2.2 %

1.19 [ 0.51, 2.80 ]

Hu 2004

6/43

5/43

1.3 %

1.20 [ 0.40, 3.64 ]

Berrutti 2008

5/61

0/57

0.2 %

10.29 [ 0.58, 182.01 ]

211

192

4.5 %

1.73 [ 0.84, 3.58 ]

100.0 %

1.20 [ 1.06, 1.37 ]

Hu 1999 Wong 2000



Total (95% CI)

1932

2039

Total events: 373 (14 days), 317 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 13.50, df = 25 (P = 0.97); I2 =0.0% Test for overall effect: Z = 2.89 (P = 0.0039) Test for subgroup differences: Chi2 = 1.78, df = 2 (P = 0.41), I2 =0.0%

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


192

Analysis 1.3. Comparison 1 PPI + two antibiotics triple therapy, 14 days versus 7 days, main analyses, Outcome 3 Patients discontinued treatment due to adverse events, subgroup by antibiotics regimens, regardless of dose. Review:


pylori eradication

Comparison: 1 PPI + two antibiotics triple therapy, 14 days versus 7 days, main analyses Outcome: 3 Patients discontinued treatment due to adverse events, subgroup by antibiotics regimens, regardless of dose

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Laine 1996

2/50

0/50

2.4 %

5.00 [ 0.25, 101.58 ]

Moayyedi 1996

2/37

0/33

2.4 %

4.47 [ 0.22, 89.94 ]

Louw 1998b

0/34

0/33

Not estimable

Louw 1998a

0/30

0/32

Not estimable

Kiyota 1999

1/69

0/78

2.2 %

3.39 [ 0.14, 81.77 ]

Yang 1999

0/50

1/45

2.2 %

0.30 [ 0.01, 7.20 ]

Nakagawa 1999

1/46

0/60

2.2 %

3.89 [ 0.16, 93.43 ]

Bhasin 2000

0/24

0/22

Maconi 2001

2/71

1/71

Hu 2004

0/80

0/62

3/121

5/109

11.1 %

0.54 [ 0.13, 2.21 ]

Riquelme 2007

1/62

1/69

2.9 %

1.11 [ 0.07, 17.42 ]

Aydin 2007

0/34

0/34

Zagari 2007

5/302

4/301

12.9 %

1.25 [ 0.34, 4.59 ]

1/17

0/15

2.3 %

2.67 [ 0.12, 60.93 ]

3/112

4/117

10.1 %

0.78 [ 0.18, 3.42 ]

Park 2009a

0/29

0/25


1/57

4/120

4.7 %

0.53 [ 0.06, 4.60 ]

1/102

0/102

2.2 %

3.00 [ 0.12, 72.79 ]

1327

1378

61.5 %

1.15 [ 0.63, 2.10 ]


Paoluzi 2006

Scaccianoce 2008 Kim 2008

Karatapanis 2011

Subtotal (95% CI)

Not estimable 3.9 %

2.00 [ 0.19, 21.56 ] Not estimable

Not estimable

Not estimable

Total events: 23 (14 days), 20 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 6.13, df = 12 (P = 0.91); I2 =0.0% Test for overall effect: Z = 0.46 (P = 0.64) 2 PPI+ clarithromycin+ a nitroimidazole

0.01

0.1

Favours 14 days

1

10

100

Favours 7 days

(Continued . . . )


193


14 days

7 days


Weight


n/N

n/N

Dal Bo’ 1998

0/33

0/66

Paoluzi 2006

7/109

8/115

22.9 %

0.92 [ 0.35, 2.46 ]

142

181

22.9 %

0.92 [ 0.35, 2.46 ]

Subtotal (95% CI)

Not estimable

Total events: 7 (14 days), 8 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 0.16 (P = 0.87) 3 PPI+ amoxicillin+ a nitroimidazole Hu 1999

0/25

0/21

Not estimable

Wong 2000

0/82

0/71

Not estimable

Pellicano 2002

3/53

0/53

Hu 2003

0/39

0/26

Not estimable

Hu 2004

0/43

0/43

Not estimable

Chaudhary 2004

0/20

0/21

Not estimable

Berrutti 2008

2/61

0/57

2.4 %

4.68 [ 0.23, 95.39 ]


1/58

4/122

4.7 %

0.53 [ 0.06, 4.60 ]

Subtotal (95% CI)

381

414

9.7 %

1.95 [ 0.36, 10.65 ]

2.6 %

7.00 [ 0.37, 132.29 ]

Total events: 6 (14 days), 4 (7 days) Heterogeneity: Tau2 = 0.44; Chi2 = 2.46, df = 2 (P = 0.29); I2 =19% Test for overall effect: Z = 0.77 (P = 0.44) 4 PPI+ amoxicillin+ a quinolone Bosques-Padilla 2004

1/39

1/37

2.9 %

0.95 [ 0.06, 14.62 ]

Ercin 2010

1/40

1/51

2.9 %

1.28 [ 0.08, 19.76 ]

79

88

5.9 %

1.10 [ 0.16, 7.62 ]

100.0 %

1.14 [ 0.71, 1.82 ]


Heterogeneity: Tau2 = 0.0; Chi2 = 0.02, df = 1 (P = 0.88); I2 =0.0% Test for overall effect: Z = 0.10 (P = 0.92)

Total (95% CI)

1929

2061


0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


194

Analysis 2.1. Comparison 2 PPI + two antibiotics triple therapy, 10 days versus 7 days, main analyses, Outcome 1 H. pylori persistence, subgroup by antibiotics regimens, regardless of dose. Review:


pylori eradication


pylori persistence, subgroup by antibiotics regimens, regardless of dose

Study or subgroup

10 days

7 days


Weight


n/N

n/N

Laine 1996

5/50

7/50

1.0 %

0.71 [ 0.24, 2.10 ]

Grade 1996

2/11

2/9

0.4 %

0.82 [ 0.14, 4.71 ]

Katicic 1997

13/58

15/55

2.8 %

0.82 [ 0.43, 1.57 ]

Ching 1998

2/37

8/149

0.5 %

1.01 [ 0.22, 4.54 ]

17/78

22/86

3.8 %

0.85 [ 0.49, 1.48 ]

Kang 2000a

23/116

32/133

5.2 %

0.82 [ 0.51, 1.32 ]

Cho 2001

17/86

21/82

3.7 %

0.77 [ 0.44, 1.36 ]

Palmas 2002

10/42

21/66

2.8 %

0.75 [ 0.39, 1.43 ]

Vakil 2004

49/202

50/200

10.0 %

0.97 [ 0.69, 1.37 ]

De Francesco 2004

23/116

33/115

5.4 %

0.69 [ 0.43, 1.10 ]

Calvet 2005a

45/221

62/237

10.3 %

0.78 [ 0.56, 1.09 ]

Gisbert 2005a

30/150

33/150

6.1 %

0.91 [ 0.59, 1.41 ]

Scaccianoce 2006

13/71

17/70

2.8 %

0.75 [ 0.40, 1.43 ]

Robles-Jara 2008

16/68

24/68

4.1 %

0.67 [ 0.39, 1.14 ]

5/27

7/25

1.1 %

0.66 [ 0.24, 1.82 ]


20/118

28/120

4.4 %

0.73 [ 0.43, 1.22 ]

Karatapanis 2011

20/103

26/102

4.4 %

0.76 [ 0.46, 1.27 ]

1554

1717

69.0 %

0.80 [ 0.70, 0.91 ]

1 PPI+ clarithromycin+ amoxicillin

Mantzaris 1999

Park 2009a

Subtotal (95% CI)

Total events: 310 (10 days), 408 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 3.00, df = 16 (P = 1.00); I2 =0.0% Test for overall effect: Z = 3.35 (P = 0.00081) 2 PPI+ clarithromycin+ a nitroimidazole Hurenkamp 2000 Di Mario 2003a

Subtotal (95% CI)

1/24

2/25

0.2 %

0.52 [ 0.05, 5.38 ]

14/47

15/52

3.1 %

1.03 [ 0.56, 1.90 ]

71

77

3.3 %

0.99 [ 0.55, 1.79 ]

0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days

(Continued . . . )


195


10 days

7 days

n/N

n/N


Weight


Total events: 15 (10 days), 17 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 0.31, df = 1 (P = 0.58); I2 =0.0% Test for overall effect: Z = 0.04 (P = 0.97) 3 PPI+ amoxicillin+ a nitroimidazole Katicic 1997

18/58

25/60

4.9 %

0.74 [ 0.46, 1.21 ]

Pellicano 2002

15/53

14/53

3.0 %

1.07 [ 0.58, 1.99 ]

Berrutti 2008

13/53

14/57

2.7 %

1.00 [ 0.52, 1.92 ]

24/117

32/122

5.4 %

0.78 [ 0.49, 1.24 ]

281

292

16.1 %

0.85 [ 0.65, 1.12 ]



Heterogeneity: Tau2 = 0.0; Chi2 = 1.17, df = 3 (P = 0.76); I2 =0.0% Test for overall effect: Z = 1.17 (P = 0.24) 4 PPI+ amoxicillin+ a quinolone Bago 2010

12/75

18/75

2.7 %

0.67 [ 0.35, 1.29 ]

Sacco 2010

9/94

20/102

2.2 %

0.49 [ 0.23, 1.02 ]

169

177

4.9 %

0.58 [ 0.36, 0.95 ]


Heterogeneity: Tau2 = 0.0; Chi2 = 0.39, df = 1 (P = 0.53); I2 =0.0% Test for overall effect: Z = 2.18 (P = 0.030) 5 PPI+ amoxicillin+ a nitrofuran Lv 2011

30/145

38/145

6.7 %

0.79 [ 0.52, 1.20 ]

145

145

6.7 %

0.79 [ 0.52, 1.20 ]

2408

100.0 %

0.80 [ 0.72, 0.89 ]

Subtotal (95% CI) Total events: 30 (10 days), 38 (7 days) Heterogeneity: not applicable

Test for overall effect: Z = 1.10 (P = 0.27)

Total (95% CI)

2220


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


196

Analysis 2.2. Comparison 2 PPI + two antibiotics triple therapy, 10 days versus 7 days, main analyses, Outcome 2 Patients with adverse events, subgroup by antibiotics regimen, regardless of dose. Review:


pylori eradication

Comparison: 2 PPI + two antibiotics triple therapy, 10 days versus 7 days, main analyses Outcome: 2 Patients with adverse events, subgroup by antibiotics regimen, regardless of dose

Study or subgroup

10 days

7 days


Weight


n/N

n/N

Laine 1996

13/50

15/50

9.9 %

0.87 [ 0.46, 1.63 ]

Ching 1998

6/37

25/149

5.9 %

0.97 [ 0.43, 2.18 ]

Mantzaris 1999

7/69

8/77

4.3 %

0.98 [ 0.37, 2.55 ]

Cho 2001

16/86

13/82

8.9 %

1.17 [ 0.60, 2.29 ]

De Francesco 2004

9/116

7/115

4.3 %

1.27 [ 0.49, 3.31 ]

Calvet 2005a

52/221

62/237

38.6 %

0.90 [ 0.65, 1.24 ]

Gisbert 2005a

15/150

13/150

7.9 %

1.15 [ 0.57, 2.34 ]

Scaccianoce 2006

9/71

7/70

4.6 %

1.27 [ 0.50, 3.22 ]

Subtotal (95% CI)

800

930

84.4 %

0.99 [ 0.79, 1.22 ]


Total events: 127 (10 days), 150 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 1.50, df = 7 (P = 0.98); I2 =0.0% Test for overall effect: Z = 0.12 (P = 0.90) 2 PPI+ clarithromycin+ a nitroimidazole Di Mario 2003a

Subtotal (95% CI)

12/47

9/52

6.7 %

1.48 [ 0.68, 3.18 ]

47

52

6.7 %

1.48 [ 0.68, 3.18 ]

1/53

0/57

0.4 %

3.22 [ 0.13, 77.41 ]

53

57

0.4 %

3.22 [ 0.13, 77.41 ]

18/75

11/75

8.6 %

1.64 [ 0.83, 3.22 ]

75

75

8.6 %

1.64 [ 0.83, 3.22 ]

Total events: 12 (10 days), 9 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 0.99 (P = 0.32) 3 PPI+ amoxicillin+ a nitroimidazole Berrutti 2008


Test for overall effect: Z = 0.72 (P = 0.47) 4 PPI+ amoxicillin+ a quinolone Bago 2010


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days

(Continued . . . )


197


10 days

7 days

n/N

n/N


Weight


Heterogeneity: not applicable Test for overall effect: Z = 1.42 (P = 0.15)

Total (95% CI)

975

100.0 %

1114

1.06 [ 0.87, 1.30 ]

Total events: 158 (10 days), 170 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 4.68, df = 10 (P = 0.91); I2 =0.0% Test for overall effect: Z = 0.61 (P = 0.54) Test for subgroup differences: Chi2 = 3.17, df = 3 (P = 0.37), I2 =5%

0.1 0.2

0.5

1

Favours 10 days

2

5

10

Favours 7 days

Analysis 2.3. Comparison 2 PPI + two antibiotics triple therapy, 10 days versus 7 days, main analyses, Outcome 3 Patients discontinued treatment due to adverse events, subgroup by antibiotics regimen, regardless of dose. Review:


pylori eradication

Comparison: 2 PPI + two antibiotics triple therapy, 10 days versus 7 days, main analyses Outcome: 3 Patients discontinued treatment due to adverse events, subgroup by antibiotics regimen, regardless of dose

Study or subgroup

10 days

7 days


Weight


n/N

n/N

Grade 1996

0/11

1/9

3.3 %

0.28 [ 0.01, 6.10 ]

Laine 1996

5/50

0/50

3.8 %

11.00 [ 0.62, 193.80 ]

Ching 1998

0/37

0/149

Vakil 2004

4/198

7/195

21.5 %

0.56 [ 0.17, 1.89 ]

2/71

2/70

8.5 %

0.99 [ 0.14, 6.81 ]

5/118

4/120

19.0 %

1.27 [ 0.35, 4.62 ]

0/27

0/25

1/103

0/102


Scaccianoce 2006 Filipec Kanizaj 2009 Park 2009a Karatapanis 2011

Not estimable

Not estimable 3.1 % 0.01

0.1

Favours 10 days

1

10

2.97 [ 0.12, 72.09 ]

100

Favours 7 days

(Continued . . . )


198


10 days

Subtotal (95% CI)

7 days

n/N

n/N

615

720


Weight

59.1 %


1.01 [ 0.49, 2.09 ]

Total events: 17 (10 days), 14 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 4.96, df = 5 (P = 0.42); I2 =0.0% Test for overall effect: Z = 0.02 (P = 0.98) 2 PPI+ clarithromycin+ a nitroimidazole Hurenkamp 2000

0/24

0/25

Di Mario 2003a

3/47

1/52

6.4 %

3.32 [ 0.36, 30.82 ]

71

77

6.4 %

3.32 [ 0.36, 30.82 ]

Subtotal (95% CI)

Not estimable

Total events: 3 (10 days), 1 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 1.06 (P = 0.29) 3 PPI+ amoxicillin+ a nitroimidazole Pellicano 2002

3/53

0/53

3.7 %

7.00 [ 0.37, 132.29 ]

Berrutti 2008

1/53

0/57

3.1 %

3.22 [ 0.13, 77.41 ]


3/117

4/122

14.5 %

0.78 [ 0.18, 3.42 ]

Subtotal (95% CI)

223

232

21.3 %

1.45 [ 0.41, 5.18 ]

Total events: 7 (10 days), 4 (7 days) Heterogeneity: Tau2 = 0.07; Chi2 = 2.09, df = 2 (P = 0.35); I2 =4% Test for overall effect: Z = 0.57 (P = 0.57) 4 PPI+ amoxicillin+ a quinolone Bago 2010

3/75

2/75

10.2 %

1.50 [ 0.26, 8.72 ]

Sacco 2010

0/94

1/102

3.1 %

0.36 [ 0.01, 8.76 ]

169

177

13.3 %

1.08 [ 0.23, 5.02 ]

100.0 %

1.18 [ 0.67, 2.06 ]



Total (95% CI)

1078

1206


0.01

0.1

Favours 10 days

1

10

100

Favours 7 days


199

Analysis 3.1. Comparison 3 PPI + two antibiotics triple therapy, 14 days versus 10 days, main analyses, Outcome 1 H. pylori persistence, subgroup by antibiotics regimen, regardless of dose. Review:


pylori eradication


pylori persistence, subgroup by antibiotics regimen, regardless of dose

Study or subgroup

14 days

10 days


Weight


n/N

n/N

Laine 1996

4/50

5/50

2.8 %

0.80 [ 0.23, 2.81 ]

Katicic 1997

9/52

13/58

6.6 %

0.77 [ 0.36, 1.66 ]

Fennerty 1998

33/136

38/148

16.1 %

0.95 [ 0.63, 1.42 ]

Mantzaris 1999

10/55

17/78

7.6 %

0.83 [ 0.41, 1.68 ]

12/138

23/116

8.5 %

0.44 [ 0.23, 0.84 ]

7/87

17/86

5.8 %

0.41 [ 0.18, 0.93 ]

Palmas 2002

18/64

10/42

8.2 %

1.18 [ 0.61, 2.30 ]

Park 2009a

4/29

5/27

3.0 %

0.74 [ 0.22, 2.49 ]


2/57

20/118

2.2 %

0.21 [ 0.05, 0.86 ]

10/102

20/103

7.5 %

0.50 [ 0.25, 1.02 ]

770

826

68.1 %

0.69 [ 0.52, 0.91 ]


Kang 2000a Cho 2001

Karatapanis 2011

Subtotal (95% CI)

Total events: 109 (14 days), 168 (10 days) Heterogeneity: Tau2 = 0.05; Chi2 = 12.32, df = 9 (P = 0.20); I2 =27% Test for overall effect: Z = 2.64 (P = 0.0084) 2 PPI+ amoxicillin+ a nitroimidazole Katicic 1997

15/62

18/58

10.0 %

0.78 [ 0.43, 1.40 ]

Pellicano 2002

14/53

15/53

9.1 %

0.93 [ 0.50, 1.74 ]

Berrutti 2008

15/61

13/53

8.6 %

1.00 [ 0.53, 1.91 ]


4/58

24/117

4.1 %

0.34 [ 0.12, 0.92 ]

Subtotal (95% CI)

234

281

31.9 %

0.79 [ 0.54, 1.15 ]

100.0 %

0.72 [ 0.58, 0.90 ]

Total events: 48 (14 days), 70 (10 days) Heterogeneity: Tau2 = 0.03; Chi2 = 3.67, df = 3 (P = 0.30); I2 =18% Test for overall effect: Z = 1.22 (P = 0.22)

Total (95% CI)

1004

1107

Total events: 157 (14 days), 238 (10 days) Heterogeneity: Tau2 = 0.03; Chi2 = 16.29, df = 13 (P = 0.23); I2 =20% Test for overall effect: Z = 2.93 (P = 0.0034) Test for subgroup differences: Chi2 = 0.35, df = 1 (P = 0.55), I2 =0.0%

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days


200

Analysis 3.2. Comparison 3 PPI + two antibiotics triple therapy, 14 days versus 10 days, main analyses, Outcome 2 Patients with adverse events, subgroup by antibiotics, regardless of dose. Review:


pylori eradication

Comparison: 3 PPI + two antibiotics triple therapy, 14 days versus 10 days, main analyses Outcome: 2 Patients with adverse events, subgroup by antibiotics, regardless of dose

Study or subgroup

14 days

10 days


Weight


n/N

n/N

14/50

13/50

14.4 %

1.08 [ 0.56, 2.05 ]

Fennerty 1998

46/136

56/148

61.2 %

0.89 [ 0.65, 1.22 ]

Mantzaris 1999

6/49

7/69

5.7 %

1.21 [ 0.43, 3.37 ]

20/87

16/86

17.4 %

1.24 [ 0.69, 2.22 ]

322

353

98.7 %

0.99 [ 0.77, 1.27 ]

1 PPI+ clarithromycin+ amoxicillin Laine 1996

Cho 2001

Subtotal (95% CI)

Total events: 86 (14 days), 92 (10 days) Heterogeneity: Tau2 = 0.0; Chi2 = 1.18, df = 3 (P = 0.76); I2 =0.0% Test for overall effect: Z = 0.08 (P = 0.93) 2 PPI+ amoxicillin+ a nitroimidazole Berrutti 2008

Subtotal (95% CI)

5/61

1/53

1.3 %

4.34 [ 0.52, 36.02 ]

61

53

1.3 %

4.34 [ 0.52, 36.02 ]

406

100.0 %

1.01 [ 0.79, 1.29 ]

Total events: 5 (14 days), 1 (10 days) Heterogeneity: not applicable Test for overall effect: Z = 1.36 (P = 0.17)

Total (95% CI)

383


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days


201

Analysis 3.3. Comparison 3 PPI + two antibiotics triple therapy, 14 days versus 10 days, main analyses, Outcome 3 Patients discontinued treatment due to adverse events, subgroup by antibiotics regimens, regardless of dose. Review:


pylori eradication

Comparison: 3 PPI + two antibiotics triple therapy, 14 days versus 10 days, main analyses Outcome: 3 Patients discontinued treatment due to adverse events, subgroup by antibiotics regimens, regardless of dose

Study or subgroup

14 days

10 days


Weight


n/N

n/N

2/50

5/50

19.0 %

0.40 [ 0.08, 1.97 ]

6/136

3/148

25.8 %

2.18 [ 0.56, 8.53 ]


1/57

5/118

10.7 %

0.41 [ 0.05, 3.46 ]

Park 2009a

0/29

0/27

1/102

1/103

6.3 %

1.01 [ 0.06, 15.93 ]

374

446

61.9 %

0.89 [ 0.36, 2.20 ]

1 PPI+ clarithromycin+ amoxicillin Laine 1996 Fennerty 1998

Karatapanis 2011

Subtotal (95% CI)

Not estimable

Total events: 10 (14 days), 14 (10 days) Heterogeneity: Tau2 = 0.04; Chi2 = 3.12, df = 3 (P = 0.37); I2 =4% Test for overall effect: Z = 0.25 (P = 0.80) 2 PPI+ amoxicillin+ a nitroimidazole Pellicano 2002

3/53

3/53

20.0 %

1.00 [ 0.21, 4.73 ]

Berrutti 2008

2/61

1/53

8.6 %

1.74 [ 0.16, 18.63 ]


1/58

3/117

9.6 %

0.67 [ 0.07, 6.32 ]

Subtotal (95% CI)

172

223

38.1 %

1.02 [ 0.33, 3.15 ]

100.0 %

0.94 [ 0.47, 1.89 ]

Total events: 6 (14 days), 7 (10 days) Heterogeneity: Tau2 = 0.0; Chi2 = 0.33, df = 2 (P = 0.85); I2 =0.0% Test for overall effect: Z = 0.04 (P = 0.97)

Total (95% CI)

546

669


0.01

0.1

Favours 14 days

1

10

100

Favours 10 days


202

Analysis 4.1. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimens. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 1 H.

pylori persistence, subgroup by regimens

Study or subgroup

14 days

7 days

n/N

n/N


Weight


1 PPI and clarithromycin and amoxicillin used twice daily at standard doses Laine 1996

4/50

7/50

1.1 %

0.57 [ 0.18, 1.83 ]

Moayyedi 1996

6/38

5/35

1.3 %

1.11 [ 0.37, 3.30 ]

Katicic 1997

9/52

15/55

2.5 %

0.63 [ 0.30, 1.32 ]

Mones 1997

4/61

5/65

1.0 %

0.85 [ 0.24, 3.03 ]

Louw 1998b

3/34

7/33

1.0 %

0.42 [ 0.12, 1.47 ]

Paoluzi 1998

6/53

16/54

1.9 %

0.38 [ 0.16, 0.90 ]

10/55

22/86

2.9 %

0.71 [ 0.36, 1.38 ]

5/26

6/25

1.4 %

0.80 [ 0.28, 2.29 ]

12/138

32/133

3.3 %

0.36 [ 0.19, 0.67 ]

Cho 2001

7/87

21/82

2.2 %

0.31 [ 0.14, 0.70 ]

Antelo 2001

5/40

4/40

1.0 %

1.25 [ 0.36, 4.32 ]

Maconi 2001

10/71

18/71

2.7 %

0.56 [ 0.28, 1.12 ]

Palmas 2002

18/64

21/66

4.1 %

0.88 [ 0.52, 1.50 ]

Gumurdulu 2004

35/59

40/53

8.4 %

0.79 [ 0.61, 1.02 ]

Hu 2004

5/41

7/40

1.3 %

0.70 [ 0.24, 2.01 ]

Lee 2004

34/342

51/328

5.7 %

0.64 [ 0.43, 0.96 ]

Keum 2005

20/179

25/96

4.1 %

0.43 [ 0.25, 0.73 ]

Paoluzi 2006

38/126

50/117

6.8 %

0.71 [ 0.50, 0.99 ]

Kim 2007

64/261

97/337

8.2 %

0.85 [ 0.65, 1.12 ]

9/62

15/69

2.4 %

0.67 [ 0.31, 1.42 ]

Aydin 2007

15/40

24/40

4.7 %

0.63 [ 0.39, 1.00 ]

Zagari 2007

56/302

62/302

7.1 %

0.90 [ 0.65, 1.25 ]

Suriani 2008

2/23

7/26

0.7 %

0.32 [ 0.07, 1.40 ]

Mantzaris 1999 Simsek 1999 Kang 2000a

Riquelme 2007

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days

(Continued . . . )


203


14 days

7 days


Weight

Continued)


n/N

n/N

5/17

7/15

1.7 %

0.63 [ 0.25, 1.57 ]

22/112

27/117

4.4 %

0.85 [ 0.52, 1.40 ]

Park 2009a

4/29

7/25

1.2 %

0.49 [ 0.16, 1.49 ]


2/57

28/120

0.8 %

0.15 [ 0.04, 0.61 ]

10/102

26/102

2.9 %

0.38 [ 0.20, 0.76 ]

2521

2582

86.9 %

0.66 [ 0.59, 0.75 ]

Scaccianoce 2008 Kim 2008

Karatapanis 2011

Subtotal (95% CI)

Total events: 420 (14 days), 652 (7 days) Heterogeneity: Tau2 = 0.02; Chi2 = 33.03, df = 27 (P = 0.20); I2 =18% Test for overall effect: Z = 6.35 (P < 0.00001) 2 PPI standard dose used once daily or low dose twice daily, clarithromycin and amoxicillin used twice daily at standard doses Louw 1998a

2/30

6/32

0.7 %

0.36 [ 0.08, 1.63 ]

Keum 2005

3/32

10/45

1.1 %

0.42 [ 0.13, 1.41 ]

Garza Gonz lez 2007

11/29

4/30

1.4 %

2.84 [ 1.02, 7.92 ]

Subtotal (95% CI)

91

107

3.2 %

0.80 [ 0.20, 3.29 ]

Total events: 16 (14 days), 20 (7 days) Heterogeneity: Tau2 = 1.14; Chi2 = 7.76, df = 2 (P = 0.02); I2 =74% Test for overall effect: Z = 0.30 (P = 0.76) 3 PPI and amoxicillin standard dose used twice daily, clarithromycin used at low dose Kiyota 1999

8/69

17/78

2.3 %

0.53 [ 0.24, 1.16 ]

Hu 2004

5/42

8/47

1.4 %

0.70 [ 0.25, 1.97 ]

111

125

3.7 %

0.59 [ 0.32, 1.09 ]


Heterogeneity: Tau2 = 0.0; Chi2 = 0.17, df = 1 (P = 0.68); I2 =0.0% Test for overall effect: Z = 1.68 (P = 0.092) 4 PPI used once daily, clarithromycin and amoxicillin both used at low dose Yang 1999

11/57

20/55

3.2 %

0.53 [ 0.28, 1.00 ]

Nakagawa 1999

10/46

14/60

2.6 %

0.93 [ 0.46, 1.90 ]

1/24

10/22

0.4 %

0.09 [ 0.01, 0.66 ]

127

137

6.2 %

0.52 [ 0.22, 1.24 ]

100.0 %

0.65 [ 0.57, 0.75 ]

Bhasin 2000



Total (95% CI)

2850

2951

Total events: 471 (14 days), 741 (7 days) Heterogeneity: Tau2 = 0.03; Chi2 = 47.68, df = 35 (P = 0.07); I2 =27% Test for overall effect: Z = 6.39 (P < 0.00001) Test for subgroup differences: Chi2 = 0.52, df = 3 (P = 0.92), I2 =0.0%

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


204

Analysis 4.2. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 2 H. pylori persistence, subgroup by location. Review:


pylori eradication


pylori persistence, subgroup by location

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Yang 1999

11/57

20/55

3.2 %

0.53 [ 0.28, 1.00 ]

Kiyota 1999

8/69

17/78

2.4 %

0.53 [ 0.24, 1.16 ]

10/46

14/60

2.7 %

0.93 [ 0.46, 1.90 ]

Simsek 1999

5/26

6/25

1.4 %

0.80 [ 0.28, 2.29 ]

Bhasin 2000

1/24

10/22

0.4 %

0.09 [ 0.01, 0.66 ]

Kang 2000a

12/138

32/133

3.3 %

0.36 [ 0.19, 0.67 ]

Cho 2001

7/87

21/82

2.3 %

0.31 [ 0.14, 0.70 ]

Hu 2004

10/83

15/87

2.5 %

0.70 [ 0.33, 1.47 ]

Gumurdulu 2004

35/59

40/53

8.1 %

0.79 [ 0.61, 1.02 ]

Lee 2004

34/342

51/328

5.6 %

0.64 [ 0.43, 0.96 ]

Keum 2005

23/211

35/141

4.7 %

0.44 [ 0.27, 0.71 ]

Aydin 2007

15/40

24/40

4.8 %

0.63 [ 0.39, 1.00 ]

Kim 2007

64/261

97/337

7.9 %

0.85 [ 0.65, 1.12 ]

Kim 2008

22/112

27/117

4.4 %

0.85 [ 0.52, 1.40 ]

4/29

7/25

1.3 %

0.49 [ 0.16, 1.49 ]

1584

1583

55.1 %

0.63 [ 0.52, 0.75 ]

1 Asian countries

Nakagawa 1999

Park 2009a

Subtotal (95% CI)

Total events: 261 (14 days), 416 (7 days) Heterogeneity: Tau2 = 0.04; Chi2 = 22.43, df = 14 (P = 0.07); I2 =38% Test for overall effect: Z = 4.99 (P < 0.00001) 2 European countries Moayyedi 1996

6/38

5/35

1.3 %

1.11 [ 0.37, 3.30 ]

Mones 1997

4/61

5/65

1.0 %

0.85 [ 0.24, 3.03 ]

Katicic 1997

9/52

15/55

2.6 %

0.63 [ 0.30, 1.32 ]

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days

(Continued . . . )


205

(. . .

Study or subgroup

14 days

7 days


Weight

Continued)


n/N

n/N

6/53

16/54

2.0 %

0.38 [ 0.16, 0.90 ]

Mantzaris 1999

10/55

22/86

3.0 %

0.71 [ 0.36, 1.38 ]

Maconi 2001

10/71

18/71

2.8 %

0.56 [ 0.28, 1.12 ]

Palmas 2002

18/64

21/66

4.2 %

0.88 [ 0.52, 1.50 ]

Paoluzi 2006

38/126

50/117

6.7 %

0.71 [ 0.50, 0.99 ]

Zagari 2007

56/302

62/302

6.9 %

0.90 [ 0.65, 1.25 ]

Suriani 2008

2/23

7/26

0.8 %

0.32 [ 0.07, 1.40 ]

Scaccianoce 2008

5/17

7/15

1.8 %

0.63 [ 0.25, 1.57 ]


2/57

28/120

0.8 %

0.15 [ 0.04, 0.61 ]

10/102

26/102

2.9 %

0.38 [ 0.20, 0.76 ]

1021

1114

36.9 %

0.66 [ 0.54, 0.82 ]

Paoluzi 1998

Karatapanis 2011

Subtotal (95% CI)

Total events: 176 (14 days), 282 (7 days) Heterogeneity: Tau2 = 0.03; Chi2 = 15.39, df = 12 (P = 0.22); I2 =22% Test for overall effect: Z = 3.82 (P = 0.00013) 3 South or North American countries Laine 1996

4/50

7/50

1.2 %

0.57 [ 0.18, 1.83 ]

Antelo 2001

5/40

4/40

1.1 %

1.25 [ 0.36, 4.32 ]

11/29

4/30

1.5 %

2.84 [ 1.02, 7.92 ]

9/62

15/69

2.5 %

0.67 [ 0.31, 1.42 ]

181

189

6.2 %

1.06 [ 0.51, 2.19 ]

Garza Gonz lez 2007 Riquelme 2007


Heterogeneity: Tau2 = 0.28; Chi2 = 6.13, df = 3 (P = 0.11); I2 =51% Test for overall effect: Z = 0.14 (P = 0.88) 4 South Africa Louw 1998b

3/34

7/33

1.0 %

0.42 [ 0.12, 1.47 ]

Louw 1998a

2/30

6/32

0.7 %

0.36 [ 0.08, 1.63 ]

64

65

1.7 %

0.39 [ 0.15, 1.03 ]

100.0 %

0.65 [ 0.57, 0.75 ]



Total (95% CI)

2850

2951


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


206

Analysis 4.3. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 3 H. pylori persistence, subgroup by baseline PUD or FD. Review:


pylori eradication


pylori persistence, subgroup by baseline PUD or FD

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Mones 1997

4/61

5/65

1.0 %

0.85 [ 0.24, 3.03 ]

Louw 1998b

3/34

7/33

1.0 %

0.42 [ 0.12, 1.47 ]

Louw 1998a

2/30

6/32

0.7 %

0.36 [ 0.08, 1.63 ]

Mantzaris 1999

10/55

22/86

2.9 %

0.71 [ 0.36, 1.38 ]

Yang 1999

11/57

20/55

3.2 %

0.53 [ 0.28, 1.00 ]

Nakagawa 1999

10/46

14/60

2.6 %

0.93 [ 0.46, 1.90 ]

Kiyota 1999

8/69

17/78

2.3 %

0.53 [ 0.24, 1.16 ]

Kang 2000a

12/138

32/133

3.3 %

0.36 [ 0.19, 0.67 ]

Maconi 2001

5/35

11/36

1.6 %

0.47 [ 0.18, 1.21 ]

Cho 2001

7/87

21/82

2.2 %

0.31 [ 0.14, 0.70 ]

18/64

21/66

4.1 %

0.88 [ 0.52, 1.50 ]

Lee 2004

34/342

51/328

5.7 %

0.64 [ 0.43, 0.96 ]

Hu 2004

10/83

15/87

2.5 %

0.70 [ 0.33, 1.47 ]

Gumurdulu 2004

35/59

40/53

8.4 %

0.79 [ 0.61, 1.02 ]

3/24

2/14

0.6 %

0.88 [ 0.17, 4.62 ]

Kim 2007

64/261

97/337

8.2 %

0.85 [ 0.65, 1.12 ]

Zagari 2007

56/302

62/302

7.1 %

0.90 [ 0.65, 1.25 ]

Kim 2008

22/112

27/117

4.4 %

0.85 [ 0.52, 1.40 ]

1859

1964

61.9 %

0.72 [ 0.63, 0.83 ]

1 PUD patients

Palmas 2002

Riquelme 2007

Subtotal (95% CI)

Total events: 314 (14 days), 470 (7 days) Heterogeneity: Tau2 = 0.01; Chi2 = 18.60, df = 17 (P = 0.35); I2 =9% Test for overall effect: Z = 4.77 (P < 0.00001) 2 FD patients

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days

(Continued . . . )


207


14 days

7 days


Weight

Continued)


n/N

n/N

Paoluzi 1998

6/53

16/54

2.0 %

0.38 [ 0.16, 0.90 ]

Maconi 2001

5/36

7/35

1.4 %

0.69 [ 0.24, 1.98 ]

Riquelme 2007

6/38

13/55

1.9 %

0.67 [ 0.28, 1.60 ]

11/29

4/30

1.4 %

2.84 [ 1.02, 7.92 ]

Scaccianoce 2008

5/17

7/15

1.8 %

0.63 [ 0.25, 1.57 ]

Suriani 2008

2/23

7/26

0.7 %

0.32 [ 0.07, 1.40 ]

196

215

9.2 %

0.70 [ 0.39, 1.26 ]

Garza Gonz lez 2007


Heterogeneity: Tau2 = 0.27; Chi2 = 10.24, df = 5 (P = 0.07); I2 =51% Test for overall effect: Z = 1.19 (P = 0.23) 3 Mixed PUD and FD, or without specifying the baseline disease Moayyedi 1996

6/38

5/35

1.3 %

1.11 [ 0.37, 3.30 ]

Laine 1996

4/50

7/50

1.1 %

0.57 [ 0.18, 1.83 ]

Katicic 1997

9/52

15/55

2.5 %

0.63 [ 0.30, 1.32 ]

Simsek 1999

5/26

6/25

1.4 %

0.80 [ 0.28, 2.29 ]

Bhasin 2000

1/24

10/22

0.4 %

0.09 [ 0.01, 0.66 ]

Antelo 2001

5/40

4/40

1.0 %

1.25 [ 0.36, 4.32 ]

Keum 2005

23/211

35/141

4.7 %

0.44 [ 0.27, 0.71 ]

Paoluzi 2006

38/126

50/117

6.8 %

0.71 [ 0.50, 0.99 ]

Aydin 2007

15/40

24/40

4.7 %

0.63 [ 0.39, 1.00 ]

Park 2009a

4/29

7/25

1.3 %

0.49 [ 0.16, 1.49 ]


2/57

28/120

0.8 %

0.15 [ 0.04, 0.61 ]

10/102

26/102

2.9 %

0.38 [ 0.20, 0.76 ]

795

772

29.0 %

0.57 [ 0.44, 0.73 ]

100.0 %

0.66 [ 0.58, 0.75 ]

Karatapanis 2011

Subtotal (95% CI)


Total (95% CI)

2850

2951

Total events: 471 (14 days), 741 (7 days) Heterogeneity: Tau2 = 0.04; Chi2 = 47.73, df = 35 (P = 0.07); I2 =27% Test for overall effect: Z = 6.31 (P < 0.00001) Test for subgroup differences: Chi2 = 2.84, df = 2 (P = 0.24), I2 =30%

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


208

Analysis 4.4. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 4 H. pylori persistence, subgroup by risk of bias: allocation concealment. Review:


pylori eradication


pylori persistence, subgroup by risk of bias: allocation concealment

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Zagari 2007

56/302

62/302

6.9 %

0.90 [ 0.65, 1.25 ]

Kim 2008

22/112

27/117

4.4 %

0.85 [ 0.52, 1.40 ]


2/57

28/120

0.8 %

0.15 [ 0.04, 0.61 ]

Subtotal (95% CI)

471

539

12.2 %

0.69 [ 0.37, 1.26 ]

1 Low risk

Total events: 80 (14 days), 117 (7 days) Heterogeneity: Tau2 = 0.18; Chi2 = 6.40, df = 2 (P = 0.04); I2 =69% Test for overall effect: Z = 1.21 (P = 0.23) 2 High risk Keum 2005

23/211

35/141

4.7 %

0.44 [ 0.27, 0.71 ]

9/62

15/69

2.5 %

0.67 [ 0.31, 1.42 ]

273

210

7.2 %

0.50 [ 0.33, 0.74 ]

Riquelme 2007


Heterogeneity: Tau2 = 0.0; Chi2 = 0.85, df = 1 (P = 0.36); I2 =0.0% Test for overall effect: Z = 3.39 (P = 0.00069) 3 Unclear risk Moayyedi 1996

6/38

5/35

1.3 %

1.11 [ 0.37, 3.30 ]

Laine 1996

4/50

7/50

1.2 %

0.57 [ 0.18, 1.83 ]

Mones 1997

4/61

5/65

1.0 %

0.85 [ 0.24, 3.03 ]

Katicic 1997

9/52

15/55

2.6 %

0.63 [ 0.30, 1.32 ]

Louw 1998a

2/30

6/32

0.7 %

0.36 [ 0.08, 1.63 ]

Paoluzi 1998

6/53

16/54

2.0 %

0.38 [ 0.16, 0.90 ]

Louw 1998b

3/34

7/33

1.0 %

0.42 [ 0.12, 1.47 ]

Simsek 1999

5/26

6/25

1.4 %

0.80 [ 0.28, 2.29 ]

10/46

14/60

2.7 %

0.93 [ 0.46, 1.90 ]

Kiyota 1999

8/69

17/78

2.4 %

0.53 [ 0.24, 1.16 ]

Yang 1999

11/57

20/55

3.2 %

0.53 [ 0.28, 1.00 ]

Nakagawa 1999

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days

(Continued . . . )


209


14 days

7 days


Weight


n/N

n/N

10/55

22/86

3.0 %

0.71 [ 0.36, 1.38 ]

Bhasin 2000

1/24

10/22

0.4 %

0.09 [ 0.01, 0.66 ]

Kang 2000a

12/138

32/133

3.3 %

0.36 [ 0.19, 0.67 ]

Maconi 2001

10/71

18/71

2.8 %

0.56 [ 0.28, 1.12 ]

Antelo 2001

5/40

4/40

1.1 %

1.25 [ 0.36, 4.32 ]

Cho 2001

7/87

21/82

2.3 %

0.31 [ 0.14, 0.70 ]

Palmas 2002

18/64

21/66

4.2 %

0.88 [ 0.52, 1.50 ]

Hu 2004

10/83

15/87

2.5 %

0.70 [ 0.33, 1.47 ]

Lee 2004

34/342

51/328

5.6 %

0.64 [ 0.43, 0.96 ]

35/59

40/53

8.1 %

0.79 [ 0.61, 1.02 ]

Paoluzi 2006

38/126

50/117

6.7 %

0.71 [ 0.50, 0.99 ]

Kim 2007

64/261

97/337

7.9 %

0.85 [ 0.65, 1.12 ]

Aydin 2007

15/40

24/40

4.8 %

0.63 [ 0.39, 1.00 ]

Garza Gonz lez 2007

11/29

4/30

1.5 %

2.84 [ 1.02, 7.92 ]

Suriani 2008

2/23

7/26

0.8 %

0.32 [ 0.07, 1.40 ]

Scaccianoce 2008

5/17

7/15

1.8 %

0.63 [ 0.25, 1.57 ]

Park 2009a

4/29

7/25

1.3 %

0.49 [ 0.16, 1.49 ]

10/102

26/102

2.9 %

0.38 [ 0.20, 0.76 ]

2106

2202

80.6 %

0.66 [ 0.57, 0.76 ]

100.0 %

0.65 [ 0.57, 0.75 ]

Mantzaris 1999

Gumurdulu 2004

Karatapanis 2011

Subtotal (95% CI)

Total events: 359 (14 days), 574 (7 days) Heterogeneity: Tau2 = 0.03; Chi2 = 35.86, df = 28 (P = 0.15); I2 =22% Test for overall effect: Z = 5.89 (P < 0.00001)

Total (95% CI)

2850

2951


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


210

Analysis 4.5. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 5 H. pylori persistence, subgroup by risk of bias: overall. Review:


pylori eradication


pylori persistence, subgroup by risk of bias: overall

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Zagari 2007

56/302

62/302

6.9 %

0.90 [ 0.65, 1.25 ]

Kim 2008

22/112

27/117

4.4 %

0.85 [ 0.52, 1.40 ]

414

419

11.4 %

0.89 [ 0.68, 1.16 ]

1 Low risk


Heterogeneity: Tau2 = 0.0; Chi2 = 0.04, df = 1 (P = 0.85); I2 =0.0% Test for overall effect: Z = 0.86 (P = 0.39) 2 High risk Moayyedi 1996

6/38

5/35

1.3 %

1.11 [ 0.37, 3.30 ]

Kiyota 1999

8/69

17/78

2.4 %

0.53 [ 0.24, 1.16 ]

Yang 1999

11/57

20/55

3.2 %

0.53 [ 0.28, 1.00 ]

Mantzaris 1999

10/55

22/86

3.0 %

0.71 [ 0.36, 1.38 ]

Nakagawa 1999

10/46

14/60

2.7 %

0.93 [ 0.46, 1.90 ]

Maconi 2001

10/71

18/71

2.8 %

0.56 [ 0.28, 1.12 ]

Palmas 2002

18/64

21/66

4.2 %

0.88 [ 0.52, 1.50 ]

Lee 2004

34/342

51/328

5.6 %

0.64 [ 0.43, 0.96 ]

Keum 2005

23/211

35/141

4.7 %

0.44 [ 0.27, 0.71 ]

Paoluzi 2006

38/126

50/117

6.7 %

0.71 [ 0.50, 0.99 ]

Kim 2007

64/261

97/337

7.9 %

0.85 [ 0.65, 1.12 ]

Riquelme 2007

9/62

15/69

2.5 %

0.67 [ 0.31, 1.42 ]

Scaccianoce 2008

5/17

7/15

1.8 %

0.63 [ 0.25, 1.57 ]

Karatapanis 2011

10/102

26/102

2.9 %

0.38 [ 0.20, 0.76 ]

1521

1560

51.7 %

0.68 [ 0.60, 0.79 ]

Subtotal (95% CI)

Total events: 256 (14 days), 398 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 12.52, df = 13 (P = 0.49); I2 =0.0% Test for overall effect: Z = 5.38 (P < 0.00001) 3 Unclear risk

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days

(Continued . . . )


211


14 days

7 days


Weight


n/N

n/N

Laine 1996

4/50

7/50

1.2 %

0.57 [ 0.18, 1.83 ]

Katicic 1997

9/52

15/55

2.6 %

0.63 [ 0.30, 1.32 ]

Mones 1997

4/61

5/65

1.0 %

0.85 [ 0.24, 3.03 ]

Louw 1998a

2/30

6/32

0.7 %

0.36 [ 0.08, 1.63 ]

Paoluzi 1998

6/53

16/54

2.0 %

0.38 [ 0.16, 0.90 ]

Louw 1998b

3/34

7/33

1.0 %

0.42 [ 0.12, 1.47 ]

Simsek 1999

5/26

6/25

1.4 %

0.80 [ 0.28, 2.29 ]

Bhasin 2000

1/24

10/22

0.4 %

0.09 [ 0.01, 0.66 ]

Kang 2000a

12/138

32/133

3.3 %

0.36 [ 0.19, 0.67 ]

Cho 2001

7/87

21/82

2.3 %

0.31 [ 0.14, 0.70 ]

Antelo 2001

5/40

4/40

1.1 %

1.25 [ 0.36, 4.32 ]

Gumurdulu 2004

35/59

40/53

8.1 %

0.79 [ 0.61, 1.02 ]

Hu 2004

10/83

15/87

2.5 %

0.70 [ 0.33, 1.47 ]

Aydin 2007

15/40

24/40

4.8 %

0.63 [ 0.39, 1.00 ]

Garza Gonz lez 2007

11/29

4/30

1.5 %

2.84 [ 1.02, 7.92 ]

Suriani 2008

2/23

7/26

0.8 %

0.32 [ 0.07, 1.40 ]


2/57

28/120

0.8 %

0.15 [ 0.04, 0.61 ]

Park 2009a

4/29

7/25

1.3 %

0.49 [ 0.16, 1.49 ]

915

972

36.9 %

0.56 [ 0.42, 0.75 ]

100.0 %

0.65 [ 0.57, 0.75 ]

Subtotal (95% CI)


Total (95% CI)

2850

2951

Total events: 471 (14 days), 741 (7 days) Heterogeneity: Tau2 = 0.04; Chi2 = 47.38, df = 33 (P = 0.05); I2 =30% Test for overall effect: Z = 6.22 (P < 0.00001) Test for subgroup differences: Chi2 = 5.27, df = 2 (P = 0.07), I2 =62%

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


212

Analysis 4.6. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 6 Patients with adverse events. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 6 Patients with adverse events

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Moayyedi 1996

31/37

18/33

16.0 %

1.54 [ 1.09, 2.16 ]

Laine 1996

14/50

15/50

5.0 %

0.93 [ 0.51, 1.72 ]

Mones 1997

9/61

7/65

2.2 %

1.37 [ 0.54, 3.45 ]

Louw 1998a

8/30

7/32

2.4 %

1.22 [ 0.50, 2.95 ]

Louw 1998b

6/34

7/33

1.9 %

0.83 [ 0.31, 2.22 ]

Kiyota 1999

23/65

16/74

6.3 %

1.64 [ 0.95, 2.82 ]

Yang 1999

9/50

8/45

2.5 %

1.01 [ 0.43, 2.40 ]

Mantzaris 1999

6/49

8/77

1.9 %

1.18 [ 0.44, 3.19 ]

Bhasin 2000

1/24

1/22

0.3 %

0.92 [ 0.06, 13.79 ]

Cho 2001

20/87

13/82

4.7 %

1.45 [ 0.77, 2.72 ]

Antelo 2001

18/39

19/39

8.5 %

0.95 [ 0.59, 1.51 ]

Maconi 2001

14/71

14/71

4.2 %

1.00 [ 0.51, 1.94 ]

Hu 2004

5/80

3/62

1.0 %

1.29 [ 0.32, 5.20 ]

Kim 2007

12/261

17/337

3.6 %

0.91 [ 0.44, 1.87 ]

Aydin 2007

13/34

12/34

4.8 %

1.08 [ 0.58, 2.02 ]

Riquelme 2007

23/62

20/69

7.7 %

1.28 [ 0.78, 2.09 ]

30/302

29/301

8.0 %

1.03 [ 0.63, 1.67 ]

5/15

3/15

1.2 %

1.67 [ 0.48, 5.76 ]

Kim 2008

24/112

18/117

6.1 %

1.39 [ 0.80, 2.42 ]

Karatapanis 2011

36/102

30/102

11.7 %

1.20 [ 0.80, 1.79 ]

Total (95% CI)

1565

1660

100.0 %

1.21 [ 1.06, 1.39 ]

Zagari 2007 Scaccianoce 2008

Total events: 307 (14 days), 265 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 8.03, df = 19 (P = 0.99); I2 =0.0% Test for overall effect: Z = 2.76 (P = 0.0058) Test for subgroup differences: Not applicable

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


213

Analysis 4.7. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 7 Patients discontinuing treatment due to adverse events. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 7 Patients discontinuing treatment due to adverse events

Study or subgroup

14 days

7 days

n/N

n/N

Laine 1996

2/50

0/50

3.9 %

5.00 [ 0.25, 101.58 ]

Moayyedi 1996

2/37

0/33

4.0 %

4.47 [ 0.22, 89.94 ]

Louw 1998a

0/30

0/32

Not estimable

Louw 1998b

0/34

0/33

Not estimable

Yang 1999

0/50

1/45

3.6 %

0.30 [ 0.01, 7.20 ]

Kiyota 1999

1/69

0/78

3.5 %

3.39 [ 0.14, 81.77 ]

Nakagawa 1999

1/46

0/60

3.5 %

3.89 [ 0.16, 93.43 ]

Bhasin 2000

0/24

0/22

Maconi 2001

2/71

1/71

Hu 2004

0/80

0/62

3/121

5/109

18.1 %

0.54 [ 0.13, 2.21 ]

Riquelme 2007

1/62

1/69

4.7 %

1.11 [ 0.07, 17.42 ]

Aydin 2007

0/34

0/34

Zagari 2007

5/302

4/301

21.0 %

1.25 [ 0.34, 4.59 ]

Kim 2008

3/112

4/117

16.5 %

0.78 [ 0.18, 3.42 ]

Scaccianoce 2008

1/17

0/15

3.7 %

2.67 [ 0.12, 60.93 ]


1/57

4/120

7.6 %

0.53 [ 0.06, 4.60 ]

Park 2009a

0/29

0/25

Karatapanis 2011

1/102

0/102

3.5 %

3.00 [ 0.12, 72.79 ]

Total (95% CI)

1327

1378

100.0 %

1.15 [ 0.63, 2.10 ]

Paoluzi 2006


Weight


Not estimable 6.3 %

2.00 [ 0.19, 21.56 ] Not estimable

Not estimable

Not estimable


0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


214

Analysis 4.8. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 8 Adverse events: Diarrhoea/ loose stool/increasing stool passage. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 8 Adverse events: Diarrhoea/ loose stool/increasing stool passage

Study or subgroup

14 days

7 days

n/N

n/N

13/37

10/33

22.0 %

1.16 [ 0.59, 2.28 ]

Yang 1999

7/50

2/45

4.4 %

3.15 [ 0.69, 14.39 ]

Nakagawa 1999

6/46

9/60

11.0 %

0.87 [ 0.33, 2.27 ]

Bhasin 2000

1/24

0/22

1.0 %

2.76 [ 0.12, 64.41 ]

Cho 2001

5/87

6/82

7.7 %

0.79 [ 0.25, 2.48 ]

Riquelme 2007

5/62

9/69

9.4 %

0.62 [ 0.22, 1.75 ]

10/302

10/301

13.6 %

1.00 [ 0.42, 2.36 ]

Kim 2007

6/261

10/337

10.1 %

0.77 [ 0.29, 2.10 ]

Kim 2008

11/112

8/117

13.2 %

1.44 [ 0.60, 3.44 ]

Scaccianoce 2008

3/15

2/15

3.8 %

1.50 [ 0.29, 7.73 ]


2/57

5/120

3.9 %

0.84 [ 0.17, 4.21 ]

1053

1201

100.0 %

1.05 [ 0.76, 1.44 ]

Moayyedi 1996

Zagari 2007

Total (95% CI)


Weight



0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


215

Analysis 4.9. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 9 Adverse event: Taste disturbance/metallic taste or glossitis. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 9 Adverse event: Taste disturbance/metallic taste or glossitis

Study or subgroup

14 days

7 days

n/N

n/N

17/37

9/33

39.3 %

1.68 [ 0.87, 3.25 ]

Yang 1999

4/50

2/45

6.3 %

1.80 [ 0.35, 9.36 ]

Cho 2001

5/87

4/82

10.4 %

1.18 [ 0.33, 4.24 ]

Kim 2007

2/261

2/337

4.5 %

1.29 [ 0.18, 9.11 ]

7/62

2/69

7.2 %

3.90 [ 0.84, 18.05 ]

10/302

7/301

18.7 %

1.42 [ 0.55, 3.69 ]

Scaccianoce 2008

2/15

1/15

3.2 %

2.00 [ 0.20, 19.78 ]


4/57

5/120

10.4 %

1.68 [ 0.47, 6.04 ]

871

1002

100.0 %

1.67 [ 1.10, 2.52 ]

Moayyedi 1996

Riquelme 2007 Zagari 2007

Total (95% CI)


Weight



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


216

Analysis 4.10. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 10 Adverse event: Nausea or vomiting. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 10 Adverse event: Nausea or vomiting

Study or subgroup

14 days

7 days

n/N

n/N

Moayyedi 1996

6/37

1/33

Yang 1999

0/50

0/45

Cho 2001

5/87

2/82

9.4 %

2.36 [ 0.47, 11.81 ]

Kim 2007

1/261

1/337

3.2 %

1.29 [ 0.08, 20.55 ]

Riquelme 2007

13/62

8/69

37.0 %

1.81 [ 0.80, 4.07 ]

Zagari 2007

3/302

0/301

2.8 %

6.98 [ 0.36, 134.49 ]

10/112

8/117

30.6 %

1.31 [ 0.53, 3.19 ]

3/57

4/120

11.4 %

1.58 [ 0.37, 6.82 ]

968

1104

100.0 %

1.81 [ 1.10, 2.96 ]

Kim 2008 Filipec Kanizaj 2009

Total (95% CI)


Weight

5.7 %

Risk Ratio MH,Random,95% CI 5.35 [ 0.68, 42.17 ] Not estimable


0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


217

Analysis 4.11. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 11 Adverse events: Skin rash and/or itching/allergic cutaneous reactions. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 11 Adverse events: Skin rash and/or itching/allergic cutaneous reactions

Study or subgroup

14 days

7 days

n/N

n/N

Nakagawa 1999

2/46

1/60

Yang 1999

0/50

0/45

Bhasin 2000

0/24

1/22

9.9 %

0.31 [ 0.01, 7.16 ]

Cho 2001

2/87

1/82

17.4 %

1.89 [ 0.17, 20.40 ]

Riquelme 2007

2/62

0/69

10.8 %

5.56 [ 0.27, 113.53 ]

Zagari 2007

2/302

4/301

34.6 %

0.50 [ 0.09, 2.70 ]

Kim 2008

1/112

0/117

9.7 %

3.13 [ 0.13, 76.10 ]

683

696

100.0 %

1.24 [ 0.46, 3.36 ]

Total (95% CI)


Weight

17.6 %



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


218

Analysis 4.12. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 12 Adverse event: Epigastric discomfort / Abdominal pain. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 12 Adverse event: Epigastric discomfort / Abdominal pain

Study or subgroup

14 days

7 days

n/N

n/N

1/50

3/45

8.9 %

0.30 [ 0.03, 2.78 ]

4/302

2/301

15.5 %

1.99 [ 0.37, 10.80 ]

8/62

10/69

59.3 %

0.89 [ 0.38, 2.11 ]

1/112

0/117

4.4 %

3.13 [ 0.13, 76.10 ]

2/57

2/120

11.8 %

2.11 [ 0.30, 14.57 ]

583

652

100.0 %

1.07 [ 0.55, 2.08 ]

Yang 1999 Zagari 2007 Riquelme 2007 Kim 2008 Filipec Kanizaj 2009

Total (95% CI)


Weight



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


219

Analysis 4.13. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 13 Adverse event: Headache. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 13 Adverse event: Headache Study or subgroup

14 days

Riquelme 2007 Zagari 2007 Filipec Kanizaj 2009

Total (95% CI)

7 days


Weight


n/N

n/N

5/62

2/69

34.8 %

2.78 [ 0.56, 13.83 ]

2/302

2/301

23.4 %

1.00 [ 0.14, 7.03 ]

3/57

4/120

41.8 %

1.58 [ 0.37, 6.82 ]

421

490

100.0 %

1.73 [ 0.67, 4.44 ]


0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


220

Analysis 4.14. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 14 Adverse event: Dry mouth/throat or thirsty. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 14 Adverse event: Dry mouth/throat or thirsty

Study or subgroup

14 days

7 days

n/N

n/N

2/46

0/60

26.3 %

6.49 [ 0.32, 131.97 ]

3/302

3/301

73.7 %

1.00 [ 0.20, 4.90 ]

348

361

100.0 %

1.63 [ 0.32, 8.38 ]

Nakagawa 1999 Zagari 2007

Total (95% CI)


Weight


Total events: 5 (14 days), 3 (7 days) Heterogeneity: Tau2 = 0.29; Chi2 = 1.19, df = 1 (P = 0.28); I2 =16% Test for overall effect: Z = 0.59 (P = 0.56) Test for subgroup differences: Not applicable

0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


221

Analysis 4.15. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 15 Adverse event: Stomatitis/Angular stomatitis. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 15 Adverse event: Stomatitis/Angular stomatitis

Study or subgroup

14 days

7 days

n/N

n/N

1/46

0/60

14.4 %

3.89 [ 0.16, 93.43 ]

5/302

4/301

85.6 %

1.25 [ 0.34, 4.59 ]

348

361

100.0 %

1.47 [ 0.44, 4.91 ]

Nakagawa 1999 Zagari 2007

Total (95% CI)


Weight



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


222

Analysis 4.16. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 16 Adverse event: Loss of appetite. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 16 Adverse event: Loss of appetite

Study or subgroup

14 days

7 days

n/N

n/N

Riquelme 2007

1/62

2/69

47.1 %

0.56 [ 0.05, 5.99 ]


1/57

3/120

52.9 %

0.70 [ 0.07, 6.60 ]

119

189

100.0 %

0.63 [ 0.12, 3.21 ]

Total (95% CI)


Weight



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


223

Analysis 4.17. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 17 Adverse event: Tongue discolouration. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 17 Adverse event: Tongue discolouration

Study or subgroup

14 days

7 days

n/N

n/N

1/302

2/301

63.8 %

0.50 [ 0.05, 5.47 ]

Riquelme 2007

0/62

1/69

36.2 %

0.37 [ 0.02, 8.93 ]

Total (95% CI)

364

370

100.0 %

0.45 [ 0.07, 3.03 ]

Zagari 2007


Weight



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


224

Analysis 4.18. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 18 Adverse event: Dizziness. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 18 Adverse event: Dizziness

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Yang 1999

2/50

1/45

50.4 %

1.80 [ 0.17, 19.19 ]

Kim 2008

1/112

2/117

49.6 %

0.52 [ 0.05, 5.68 ]

162

162

100.0 %

0.97 [ 0.18, 5.23 ]

Total (95% CI) Total events: 3 (14 days), 3 (7 days)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.52, df = 1 (P = 0.47); I2 =0.0% Test for overall effect: Z = 0.03 (P = 0.98) Test for subgroup differences: Not applicable

0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


225

Analysis 4.19. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 19 Adverse event: Regurgitation/belching. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 19 Adverse event: Regurgitation/belching

Study or subgroup

14 days

7 days

n/N

n/N

Nakagawa 1999

0/46

1/60

42.7 %

0.43 [ 0.02, 10.38 ]

Yang 1999

1/50

1/45

57.3 %

0.90 [ 0.06, 13.97 ]

96

105

100.0 %

0.66 [ 0.08, 5.25 ]

Total (95% CI)


Weight



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


226

Analysis 4.20. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 20 Adverse event: Bloating. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 20 Adverse event: Bloating

Study or subgroup

14 days

7 days

n/N

n/N

Nakagawa 1999

2/46

0/60

50.0 %

6.49 [ 0.32, 131.97 ]

Yang 1999

0/50

2/45

50.0 %

0.18 [ 0.01, 3.66 ]

96

105

100.0 %

1.08 [ 0.03, 36.21 ]

Total (95% CI)


Weight



0.001 0.01 0.1 Favours 14 days

1

10 100 1000 Favours 7 days

Analysis 4.21. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 21 Adverse event: Discolored faeces. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 21 Adverse event: Discolored faeces

Study or subgroup

14 days

7 days

n/N

n/N

Riquelme 2007

1/62

1/69


Risk Ratio MH,Random,95% CI 1.11 [ 0.07, 17.42 ]

0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

227

Analysis 4.22. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 22 Adverse event: Monilia. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 22 Adverse event: Monilia

Study or subgroup

Zagari 2007

14 days

7 days

n/N

n/N

1/302

1/301



0.01

0.1

1

Favours 14 days

10

100

Favours 7 days

Analysis 4.23. Comparison 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 23 Adverse event: Herpes simplex labialis. Review:


pylori eradication

Comparison: 4 PPI + clarithromycin + amoxicillin triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 23 Adverse event: Herpes simplex labialis

Study or subgroup

Zagari 2007

14 days

7 days

n/N

n/N

1/302

0/301



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

228

Analysis 5.1. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimen. Review:


pylori eradication


pylori persistence, subgroup by regimen

Study or subgroup

10 days

7 days

n/N

n/N


Weight


1 PPI and clarithromycin and amoxicillin used twice daily and at standard doses Laine 1996

5/50

7/50

1.5 %

0.71 [ 0.24, 2.10 ]

Grade 1996

2/11

2/9

0.6 %

0.82 [ 0.14, 4.71 ]

Katicic 1997

13/58

15/55

4.1 %

0.82 [ 0.43, 1.57 ]

Ching 1998

2/37

8/149

0.7 %

1.01 [ 0.22, 4.54 ]

17/78

22/86

5.5 %

0.85 [ 0.49, 1.48 ]

Kang 2000a

23/116

32/133

7.6 %

0.82 [ 0.51, 1.32 ]

Cho 2001

17/86

21/82

5.4 %

0.77 [ 0.44, 1.36 ]

Palmas 2002

10/42

21/66

4.1 %

0.75 [ 0.39, 1.43 ]

Vakil 2004

49/202

50/200

14.5 %

0.97 [ 0.69, 1.37 ]

De Francesco 2004

23/116

33/115

7.8 %

0.69 [ 0.43, 1.10 ]

Calvet 2005a

45/221

62/237

14.9 %

0.78 [ 0.56, 1.09 ]

Scaccianoce 2006

13/71

17/70

4.1 %

0.75 [ 0.40, 1.43 ]

Robles-Jara 2008

16/68

24/68

5.9 %

0.67 [ 0.39, 1.14 ]


20/118

28/120

6.4 %

0.73 [ 0.43, 1.22 ]

Karatapanis 2011

20/103

26/102

6.4 %

0.76 [ 0.46, 1.27 ]

1377

1542

89.5 %

0.79 [ 0.69, 0.91 ]

Mantzaris 1999

Subtotal (95% CI)

Total events: 275 (10 days), 368 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 2.52, df = 14 (P = 1.00); I2 =0.0% Test for overall effect: Z = 3.30 (P = 0.00097) 2 PPI used high dose twice daily, clarithromycin and amoxicillin used twice daily and at standard doses Gisbert 2005a

30/150

33/150

8.8 %

0.91 [ 0.59, 1.41 ]

150

150

8.8 %

0.91 [ 0.59, 1.41 ]


Test for overall effect: Z = 0.42 (P = 0.67) 3 PPI unclear dose twice daily, clarithromycin and amoxicillin used twice daily and at standard doses

0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days

(Continued . . . )


229


Park 2009a

10 days

7 days


Weight


n/N

n/N

5/27

7/25

1.7 %

0.66 [ 0.24, 1.82 ]

27

25

1.7 %

0.66 [ 0.24, 1.82 ]

1717

100.0 %

0.80 [ 0.70, 0.91 ]



Total (95% CI)

1554


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


230

Analysis 5.2. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 2 H. pylori persistence, subgroup by location. Review:


pylori eradication



Study or subgroup

10 days

7 days


Weight


n/N

n/N

Ching 1998

2/37

8/149

0.7 %

1.01 [ 0.22, 4.54 ]

Kang 2000a

23/116

32/133

7.6 %

0.82 [ 0.51, 1.32 ]

Cho 2001

17/86

21/82

5.4 %

0.77 [ 0.44, 1.36 ]

Park 2009a

5/27

7/25

1.7 %

0.66 [ 0.24, 1.82 ]

266

389

15.3 %

0.79 [ 0.57, 1.11 ]

1 Asian countries


Heterogeneity: Tau2 = 0.0; Chi2 = 0.25, df = 3 (P = 0.97); I2 =0.0% Test for overall effect: Z = 1.36 (P = 0.18) 2 European countries Katicic 1997

13/58

15/55

4.1 %

0.82 [ 0.43, 1.57 ]

Mantzaris 1999

17/78

22/86

5.5 %

0.85 [ 0.49, 1.48 ]

Palmas 2002

10/42

21/66

4.1 %

0.75 [ 0.39, 1.43 ]

De Francesco 2004

23/116

33/115

7.8 %

0.69 [ 0.43, 1.10 ]

Gisbert 2005a

30/150

33/150

8.8 %

0.91 [ 0.59, 1.41 ]

Calvet 2005a

45/221

62/237

14.9 %

0.78 [ 0.56, 1.09 ]

13/71

17/70

4.1 %

0.75 [ 0.40, 1.43 ]


20/118

28/120

6.4 %

0.73 [ 0.43, 1.22 ]

Karatapanis 2011

20/103

26/102

6.4 %

0.76 [ 0.46, 1.27 ]

957

1001

62.2 %

0.78 [ 0.66, 0.92 ]

Scaccianoce 2006

Subtotal (95% CI)

Total events: 191 (10 days), 257 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 0.96, df = 8 (P = 1.00); I2 =0.0% Test for overall effect: Z = 2.92 (P = 0.0035) 3 South or North American Grade 1996

2/11

2/9

0.6 %

0.82 [ 0.14, 4.71 ]

Laine 1996

5/50

7/50

1.5 %

0.71 [ 0.24, 2.10 ]

49/202

50/200

14.5 %

0.97 [ 0.69, 1.37 ]

Vakil 2004

0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days

(Continued . . . )


231


10 days

Robles-Jara 2008

Subtotal (95% CI)

7 days


Weight


n/N

n/N

16/68

24/68

5.9 %

0.67 [ 0.39, 1.14 ]

331

327

22.5 %

0.86 [ 0.65, 1.13 ]

100.0 %

0.80 [ 0.70, 0.91 ]


Total (95% CI)

1554

1717


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


232

Analysis 5.3. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 3 H. pylori persistence, subgroup by baseline PUD or FD. Review:


pylori eradication



Study or subgroup

10 days

7 days


Weight


n/N

n/N

0/11

5/84

0.2 %

0.64 [ 0.04, 10.93 ]

17/78

22/86

5.5 %

0.85 [ 0.49, 1.48 ]

Kang 2000a

23/116

32/133

7.5 %

0.82 [ 0.51, 1.32 ]

Cho 2001

17/86

21/82

5.3 %

0.77 [ 0.44, 1.36 ]

Palmas 2002

10/42

21/66

4.1 %

0.75 [ 0.39, 1.43 ]

25/100

21/103

6.5 %

1.23 [ 0.74, 2.04 ]

2/34

8/48

0.8 %

0.35 [ 0.08, 1.56 ]

Gisbert 2005a

30/150

33/150

8.8 %

0.91 [ 0.59, 1.41 ]

Calvet 2005a

27/142

36/161

8.6 %

0.85 [ 0.54, 1.33 ]

759

913

47.3 %

0.87 [ 0.72, 1.05 ]

1 PUD patients Ching 1998 Mantzaris 1999

Vakil 2004 De Francesco 2004

Subtotal (95% CI)

Total events: 151 (10 days), 199 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 3.69, df = 8 (P = 0.88); I2 =0.0% Test for overall effect: Z = 1.47 (P = 0.14) 2 FD patients Grade 1996

2/11

2/9

0.6 %

0.82 [ 0.14, 4.71 ]

Ching 1998

2/26

3/65

0.6 %

1.67 [ 0.30, 9.41 ]

24/102

29/97

7.9 %

0.79 [ 0.49, 1.25 ]

De Francesco 2004

21/82

25/67

7.3 %

0.69 [ 0.42, 1.11 ]

Calvet 2005a

18/79

26/76

6.5 %

0.67 [ 0.40, 1.11 ]

Scaccianoce 2006

13/71

17/70

4.1 %

0.75 [ 0.40, 1.43 ]

Subtotal (95% CI)

371

384

26.9 %

0.74 [ 0.57, 0.95 ]

1.5 %

0.71 [ 0.24, 2.10 ]

Vakil 2004

Total events: 80 (10 days), 102 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 1.19, df = 5 (P = 0.95); I2 =0.0% Test for overall effect: Z = 2.39 (P = 0.017) 3 Mixed PUD and FD, or without specifying the baseline disease Laine 1996

5/50

7/50 0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days

(Continued . . . )


233


10 days

7 days


Weight


n/N

n/N

Katicic 1997

13/58

15/55

4.1 %

0.82 [ 0.43, 1.57 ]

Robles-Jara 2008

16/68

24/68

5.9 %

0.67 [ 0.39, 1.14 ]

5/27

7/25

1.7 %

0.66 [ 0.24, 1.82 ]


20/118

28/120

6.4 %

0.73 [ 0.43, 1.22 ]

Karatapanis 2011

20/103

26/102

6.4 %

0.76 [ 0.46, 1.27 ]

424

420

25.9 %

0.73 [ 0.57, 0.94 ]

100.0 %

0.79 [ 0.70, 0.90 ]

Park 2009a



Total (95% CI)

1554

1717


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


234

Analysis 5.4. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 4 H. pylori persistence, subgroup by risk of bias: allocation concealment. Review:


pylori eradication



Study or subgroup

10 days

7 days


Weight


n/N

n/N

Vakil 2004

49/202

50/200

14.5 %

0.97 [ 0.69, 1.37 ]

Calvet 2005a

45/221

62/237

14.9 %

0.78 [ 0.56, 1.09 ]


20/118

28/120

6.4 %

0.73 [ 0.43, 1.22 ]

541

557

35.9 %

0.84 [ 0.68, 1.04 ]

1 Low risk

Subtotal (95% CI)

Total events: 114 (10 days), 140 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 1.19, df = 2 (P = 0.55); I2 =0.0% Test for overall effect: Z = 1.56 (P = 0.12) 2 Unclear risk Laine 1996

5/50

7/50

1.5 %

0.71 [ 0.24, 2.10 ]

Grade 1996

2/11

2/9

0.6 %

0.82 [ 0.14, 4.71 ]

Katicic 1997

13/58

15/55

4.1 %

0.82 [ 0.43, 1.57 ]

Ching 1998

2/37

8/149

0.7 %

1.01 [ 0.22, 4.54 ]

17/78

22/86

5.5 %

0.85 [ 0.49, 1.48 ]

Kang 2000a

23/116

32/133

7.6 %

0.82 [ 0.51, 1.32 ]

Cho 2001

17/86

21/82

5.4 %

0.77 [ 0.44, 1.36 ]

Palmas 2002

10/42

21/66

4.1 %

0.75 [ 0.39, 1.43 ]

23/116

33/115

7.8 %

0.69 [ 0.43, 1.10 ]

Scaccianoce 2006

13/71

17/70

4.1 %

0.75 [ 0.40, 1.43 ]

Robles-Jara 2008

16/68

24/68

5.9 %

0.67 [ 0.39, 1.14 ]

5/27

7/25

1.7 %

0.66 [ 0.24, 1.82 ]

20/103

26/102

6.4 %

0.76 [ 0.46, 1.27 ]

863

1010

55.3 %

0.76 [ 0.64, 0.91 ]

Mantzaris 1999

De Francesco 2004

Park 2009a Karatapanis 2011

Subtotal (95% CI)

Total events: 166 (10 days), 235 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 0.95, df = 12 (P = 1.00); I2 =0.0% Test for overall effect: Z = 3.07 (P = 0.0021) 3 High risk

0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days

(Continued . . . )


235

(. . . 10 days n/N

n/N

Gisbert 2005a

30/150

33/150

8.8 %

0.91 [ 0.59, 1.41 ]

150

150

8.8 %

0.91 [ 0.59, 1.41 ]

1717

100.0 %

0.80 [ 0.70, 0.91 ]

Subtotal (95% CI)

7 days


Weight


Study or subgroup


Total (95% CI)

1554


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


236

Analysis 5.5. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 5 H. pylori persistence, subgroup by risk of bias: overall. Review:


pylori eradication



Study or subgroup

10 days

7 days


Weight


n/N

n/N

2/37

8/149

0.7 %

1.01 [ 0.22, 4.54 ]

Mantzaris 1999

17/78

22/86

5.5 %

0.85 [ 0.49, 1.48 ]

Palmas 2002

10/42

21/66

4.1 %

0.75 [ 0.39, 1.43 ]

Gisbert 2005a

30/150

33/150

8.8 %

0.91 [ 0.59, 1.41 ]

Calvet 2005a

45/221

62/237

14.9 %

0.78 [ 0.56, 1.09 ]

Scaccianoce 2006

13/71

17/70

4.1 %

0.75 [ 0.40, 1.43 ]

Robles-Jara 2008

16/68

24/68

5.9 %

0.67 [ 0.39, 1.14 ]

Karatapanis 2011

20/103

26/102

6.4 %

0.76 [ 0.46, 1.27 ]

770

928

50.5 %

0.79 [ 0.66, 0.95 ]

1 High risk Ching 1998

Subtotal (95% CI)

Total events: 153 (10 days), 213 (7 days) Heterogeneity: Tau2 = 0.0; Chi2 = 1.02, df = 7 (P = 0.99); I2 =0.0% Test for overall effect: Z = 2.53 (P = 0.011) 2 Unclear risk Grade 1996

2/11

2/9

0.6 %

0.82 [ 0.14, 4.71 ]

Laine 1996

5/50

7/50

1.5 %

0.71 [ 0.24, 2.10 ]

Katicic 1997

13/58

15/55

4.1 %

0.82 [ 0.43, 1.57 ]

Kang 2000a

23/116

32/133

7.6 %

0.82 [ 0.51, 1.32 ]

Cho 2001

17/86

21/82

5.4 %

0.77 [ 0.44, 1.36 ]

De Francesco 2004

23/116

33/115

7.8 %

0.69 [ 0.43, 1.10 ]

Vakil 2004

49/202

50/200

14.5 %

0.97 [ 0.69, 1.37 ]


20/118

28/120

6.4 %

0.73 [ 0.43, 1.22 ]

5/27

7/25

1.7 %

0.66 [ 0.24, 1.82 ]

784

789

49.5 %

0.81 [ 0.67, 0.98 ]

Park 2009a

Subtotal (95% CI)


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days

(Continued . . . )


237


Total (95% CI)

10 days

7 days

n/N

n/N

1554

1717


Weight

100.0 %

Continued)


0.80 [ 0.70, 0.91 ]


0.1 0.2

0.5

1

Favours 10 days

2

5

10

Favours 7 days

Analysis 5.6. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 6 Patients with adverse events. Review:


pylori eradication

Comparison: 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 6 Patients with adverse events

Study or subgroup

10 days

7 days


Weight


n/N

n/N

Laine 1996

13/50

15/50

11.8 %

0.87 [ 0.46, 1.63 ]

Ching 1998

6/37

25/149

7.0 %

0.97 [ 0.43, 2.18 ]

Mantzaris 1999

7/69

8/77

5.1 %

0.98 [ 0.37, 2.55 ]

Cho 2001

16/86

13/82

10.5 %

1.17 [ 0.60, 2.29 ]

De Francesco 2004

9/116

7/115

5.1 %

1.27 [ 0.49, 3.31 ]

Calvet 2005a

52/221

62/237

45.7 %

0.90 [ 0.65, 1.24 ]

Gisbert 2005a

15/150

13/150

9.3 %

1.15 [ 0.57, 2.34 ]

Scaccianoce 2006

9/71

7/70

5.4 %

1.27 [ 0.50, 3.22 ]

Total (95% CI)

800

930

100.0 %

0.99 [ 0.79, 1.22 ]


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


238

Analysis 5.7. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 7 Patients discontinuing treatment due to adverse events. Review:


pylori eradication

Comparison: 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 7 Patients discontinuing treatment due to adverse events

Study or subgroup

10 days

7 days

n/N

n/N

Laine 1996

5/50

0/50

6.5 %

11.00 [ 0.62, 193.80 ]

Grade 1996

0/11

1/9

5.6 %

0.28 [ 0.01, 6.10 ]

Ching 1998

0/37

0/149

Vakil 2004

4/198

7/195

36.3 %

0.56 [ 0.17, 1.89 ]

2/71

2/70

14.3 %

0.99 [ 0.14, 6.81 ]

5/118

4/120

32.1 %

1.27 [ 0.35, 4.62 ]

0/27

0/25

Karatapanis 2011

1/103

0/102

5.2 %

2.97 [ 0.12, 72.09 ]

Total (95% CI)

615

720

100.0 %

1.01 [ 0.49, 2.09 ]

Scaccianoce 2006 Filipec Kanizaj 2009 Park 2009a


Weight


Not estimable

Not estimable


0.01

0.1

Favours 10 days

1

10

100

Favours 7 days


239

Analysis 5.8. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 8 Adverse events: Taste disturbance or glossitis. Review:


pylori eradication

Comparison: 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 8 Adverse events: Taste disturbance or glossitis

Study or subgroup

10 days

7 days

n/N

n/N

Ching 1998

4/37

22/149

21.7 %

0.73 [ 0.27, 2.00 ]

Cho 2001

6/86

4/82

14.4 %

1.43 [ 0.42, 4.89 ]

Vakil 2004

20/198

11/195

43.4 %

1.79 [ 0.88, 3.64 ]

De Francesco 2004

3/116

1/115

4.3 %

2.97 [ 0.31, 28.17 ]


6/118

5/120

16.2 %

1.22 [ 0.38, 3.89 ]

555

661

100.0 %

1.37 [ 0.86, 2.19 ]

Total (95% CI)


Weight



0.01

0.1

Favours 10 days

1

10

100

Favours 7 days


240

Analysis 5.9. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 9 Adverse event: Diarrhoea. Review:


pylori eradication

Comparison: 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 9 Adverse event: Diarrhoea Study or subgroup

10 days

7 days


Weight


n/N

n/N

Ching 1998

4/37

15/149

17.3 %

1.07 [ 0.38, 3.05 ]

Cho 2001

5/86

6/82

14.3 %

0.79 [ 0.25, 2.50 ]

3/116

3/115

7.6 %

0.99 [ 0.20, 4.81 ]

16/198

19/195

46.8 %

0.83 [ 0.44, 1.56 ]

6/118

5/120

14.0 %

1.22 [ 0.38, 3.89 ]

555

661

100.0 %

0.92 [ 0.60, 1.42 ]

De Francesco 2004 Vakil 2004 Filipec Kanizaj 2009

Total (95% CI)


0.01

0.1

Favours 10 days

1

10

100

Favours 7 days


241

Analysis 5.10. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 10 Adverse event: Nausea or Vomiting. Review:


pylori eradication

Comparison: 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 10 Adverse event: Nausea or Vomiting

Study or subgroup

10 days

7 days


Weight


n/N

n/N

4/86

2/82

14.6 %

1.91 [ 0.36, 10.13 ]

De Francesco 2004

0/116

1/115

4.0 %

0.33 [ 0.01, 8.03 ]

Vakil 2004

8/198

14/195

56.9 %

0.56 [ 0.24, 1.31 ]


5/118

4/120

24.5 %

1.27 [ 0.35, 4.62 ]

518

512

100.0 %

0.80 [ 0.42, 1.52 ]

Cho 2001

Total (95% CI)


0.01

0.1

Favours 10 days

1

10

100

Favours 7 days


242

Analysis 5.11. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 11 Adverse event: Abdominal pain. Review:


pylori eradication

Comparison: 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 11 Adverse event: Abdominal pain

Study or subgroup

10 days

7 days


Weight


n/N

n/N

15/198

11/195

78.1 %

1.34 [ 0.63, 2.85 ]

De Francesco 2004

2/116

1/115

7.8 %

1.98 [ 0.18, 21.56 ]


3/118

2/120

14.1 %

1.53 [ 0.26, 8.97 ]

432

430

100.0 %

1.41 [ 0.72, 2.74 ]

Vakil 2004

Total (95% CI)


0.01

0.1

Favours 10 days

1

10

100

Favours 7 days


243

Analysis 5.12. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 12 Adverse event: Skin rash or pruritus. Review:


pylori eradication

Comparison: 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 12 Adverse event: Skin rash or pruritus

Study or subgroup

10 days

7 days


Weight


n/N

n/N

Ching 1998

0/37

1/149

30.1 %

1.32 [ 0.05, 31.66 ]

Cho 2001

1/86

1/82

40.1 %

0.95 [ 0.06, 14.99 ]

1/116

0/115

29.9 %

2.97 [ 0.12, 72.26 ]

239

346

100.0 %

1.48 [ 0.26, 8.44 ]

De Francesco 2004



0.01

0.1

Favours 10 days

1

10

100

Favours 7 days


244

Analysis 5.13. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 13 Adverse event: Headache. Review:


pylori eradication

Comparison: 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 13 Adverse event: Headache

Study or subgroup

Vakil 2004 Filipec Kanizaj 2009

Total (95% CI)

10 days

7 days


Weight


n/N

n/N

16/198

9/195

74.7 %

1.75 [ 0.79, 3.87 ]

4/118

4/120

25.3 %

1.02 [ 0.26, 3.97 ]

316

315

100.0 %

1.53 [ 0.77, 3.03 ]


0.01

0.1

Favours 10 days

1

10

100

Favours 7 days


245

Analysis 5.14. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 14 Adverse event: Dyspepsia or worsened dyspepsia. Review:


pylori eradication

Comparison: 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 14 Adverse event: Dyspepsia or worsened dyspepsia

Study or subgroup

Ching 1998 Vakil 2004

Total (95% CI)

10 days

7 days

Odds Ratio MH,Random,95% CI

Weight


n/N

n/N

1/37

3/149

9.7 %

1.35 [ 0.14, 13.38 ]

11/198

22/195

90.3 %

0.46 [ 0.22, 0.98 ]

235

344

100.0 %

0.51 [ 0.25, 1.05 ]


0.01

0.1

Favours 10 days

1

10

100

Favours 7 days

Analysis 5.15. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 15 Adverse event: Flatulence. Review:


pylori eradication

Comparison: 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 15 Adverse event: Flatulence

Study or subgroup

Vakil 2004

10 days

7 days

n/N

n/N

9/198

14/195



0.1 0.2

0.5

Favours 10 days


1

2

5

10

Favours 7 days

246

Analysis 5.16. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 16 Adverse event: Infection. Review:


pylori eradication

Comparison: 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 16 Adverse event: Infection

Study or subgroup

Vakil 2004

10 days

7 days

n/N

n/N

7/198

4/195



0.1 0.2

0.5

1

Favours 10 days

2

5

10

Favours 7 days

Analysis 5.17. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 17 Adverse event: Anorexia. Review:


pylori eradication

Comparison: 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 17 Adverse event: Anorexia

Study or subgroup

Vakil 2004

10 days

7 days

n/N

n/N

6/198

5/195



0.1 0.2

0.5

Favours 10 days


1

2

5

10

Favours 7 days

247

Analysis 5.18. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 18 Adverse event: Loss appetite. Review:


pylori eradication

Comparison: 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 18 Adverse event: Loss appetite

Study or subgroup

10 days

7 days

n/N

n/N

3/118

3/120




0.1 0.2

0.5

1

Favours 10 days

2

5

10

Favours 7 days

Analysis 5.19. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 19 Adverse event: Erythaema. Review:


pylori eradication

Comparison: 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 19 Adverse event: Erythaema

Study or subgroup

De Francesco 2004

10 days

7 days

n/N

n/N

0/116

1/115



0.01

0.1

Favours 10 days


1

10

100

Favours 7 days

248

Analysis 5.20. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 20 Adverse event: Candidiasis. Review:


pylori eradication

Comparison: 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 20 Adverse event: Candidiasis

Study or subgroup

Ching 1998

10 days

7 days

n/N

n/N

0/37

1/149



0.01

0.1

1

Favours 10 days

10

100

Favours 7 days

Analysis 5.21. Comparison 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 21 Adverse event: Authors’ defined ”serious adverse events“. Review:


pylori eradication

Comparison: 5 PPI + clarithromycin + amoxicillin triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 21 Adverse event: Authors’ defined ”serious adverse events”

Study or subgroup

Vakil 2004

10 days

7 days

n/N

n/N

4/198

3/195



0.1 0.2

0.5

Favours 10 days


1

2

5

10

Favours 7 days

249

Analysis 6.1. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimen. Review:


pylori eradication

Comparison: 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses Outcome: 1 H.


Study or subgroup

14 days

10 days

n/N

n/N


Weight


1 PPI and two antibiotics used twice daily at standard doses Laine 1996

4/50

5/50

4.4 %

0.80 [ 0.23, 2.81 ]

Katicic 1997

9/52

13/58

10.0 %

0.77 [ 0.36, 1.66 ]

Fennerty 1998

33/136

38/148

21.5 %

0.95 [ 0.63, 1.42 ]

Mantzaris 1999

10/55

17/78

11.3 %

0.83 [ 0.41, 1.68 ]

12/138

23/116

12.5 %

0.44 [ 0.23, 0.84 ]

7/87

17/86

8.8 %

0.41 [ 0.18, 0.93 ]

18/64

10/42

12.1 %

1.18 [ 0.61, 2.30 ]

2/57

20/118

3.5 %

0.21 [ 0.05, 0.86 ]

10/102

20/103

11.1 %

0.50 [ 0.25, 1.02 ]

741

799

95.3 %

0.68 [ 0.50, 0.92 ]

Kang 2000a Cho 2001 Palmas 2002 Filipec Kanizaj 2009 Karatapanis 2011

Subtotal (95% CI)

Total events: 105 (14 days), 163 (10 days) Heterogeneity: Tau2 = 0.07; Chi2 = 12.32, df = 8 (P = 0.14); I2 =35% Test for overall effect: Z = 2.52 (P = 0.012) 2 PPI type and dose not clear, antibiotics used twice daily at standard doses Park 2009a

Subtotal (95% CI)

4/29

5/27

4.7 %

0.74 [ 0.22, 2.49 ]

29

27

4.7 %

0.74 [ 0.22, 2.49 ]

826

100.0 %

0.69 [ 0.52, 0.91 ]


Total (95% CI)

770


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days


250

Analysis 6.2. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 2 H. pylori persistence, subgroup by location. Review:


pylori eradication



Study or subgroup

14 days

10 days


Weight


n/N

n/N

12/138

23/116

12.5 %

0.44 [ 0.23, 0.84 ]

Cho 2001

7/87

17/86

8.8 %

0.41 [ 0.18, 0.93 ]

Park 2009a

4/29

5/27

4.7 %

0.74 [ 0.22, 2.49 ]

254

229

26.0 %

0.46 [ 0.29, 0.74 ]

1 Asian countries Kang 2000a

Subtotal (95% CI)

Total events: 23 (14 days), 45 (10 days) Heterogeneity: Tau2 = 0.0; Chi2 = 0.72, df = 2 (P = 0.70); I2 =0.0% Test for overall effect: Z = 3.19 (P = 0.0014) 2 European countries 9/52

13/58

10.0 %

0.77 [ 0.36, 1.66 ]

Mantzaris 1999

10/55

17/78

11.3 %

0.83 [ 0.41, 1.68 ]

Palmas 2002

18/64

10/42

12.1 %

1.18 [ 0.61, 2.30 ]

2/57

20/118

3.5 %

0.21 [ 0.05, 0.86 ]

10/102

20/103

11.1 %

0.50 [ 0.25, 1.02 ]

330

399

48.1 %

0.71 [ 0.45, 1.11 ]

Katicic 1997

Filipec Kanizaj 2009 Karatapanis 2011

Subtotal (95% CI)

Total events: 49 (14 days), 80 (10 days) Heterogeneity: Tau2 = 0.10; Chi2 = 6.47, df = 4 (P = 0.17); I2 =38% Test for overall effect: Z = 1.51 (P = 0.13) 3 North American countries 4/50

5/50

4.4 %

0.80 [ 0.23, 2.81 ]

33/136

38/148

21.5 %

0.95 [ 0.63, 1.42 ]

186

198

25.9 %

0.93 [ 0.63, 1.37 ]

100.0 %

0.69 [ 0.52, 0.91 ]

Laine 1996 Fennerty 1998

Subtotal (95% CI)


Total (95% CI)

770

826

Total events: 109 (14 days), 168 (10 days) Heterogeneity: Tau2 = 0.05; Chi2 = 12.32, df = 9 (P = 0.20); I2 =27% Test for overall effect: Z = 2.64 (P = 0.0084) Test for subgroup differences: Chi2 = 5.01, df = 2 (P = 0.08), I2 =60%

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days


251

Analysis 6.3. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 3 H. pylori persistence, subgroup by baseline PUD or FD. Review:


pylori eradication



Study or subgroup

14 days

10 days


Weight


n/N

n/N

Fennerty 1998

33/136

38/148

21.5 %

0.95 [ 0.63, 1.42 ]

Mantzaris 1999

10/55

17/78

11.3 %

0.83 [ 0.41, 1.68 ]

12/138

23/116

12.5 %

0.44 [ 0.23, 0.84 ]

7/87

17/86

8.8 %

0.41 [ 0.18, 0.93 ]

18/64

10/42

12.1 %

1.18 [ 0.61, 2.30 ]

480

470

66.2 %

0.73 [ 0.50, 1.09 ]

1 PUD patients

Kang 2000a Cho 2001 Palmas 2002

Subtotal (95% CI)

Total events: 80 (14 days), 105 (10 days) Heterogeneity: Tau2 = 0.10; Chi2 = 7.82, df = 4 (P = 0.10); I2 =49% Test for overall effect: Z = 1.54 (P = 0.12) 2 Mixed PUD and FD, or without specifying the baseline disease Laine 1996

4/50

5/50

4.4 %

0.80 [ 0.23, 2.81 ]

Katicic 1997

9/52

13/58

10.0 %

0.77 [ 0.36, 1.66 ]

Park 2009a

4/29

5/27

4.7 %

0.74 [ 0.22, 2.49 ]


2/57

20/118

3.5 %

0.21 [ 0.05, 0.86 ]

10/102

20/103

11.1 %

0.50 [ 0.25, 1.02 ]

290

356

33.8 %

0.59 [ 0.38, 0.90 ]

100.0 %

0.69 [ 0.52, 0.91 ]

Karatapanis 2011

Subtotal (95% CI)


Total (95% CI)

770

826


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days


252

Analysis 6.4. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 4 H. pylori persistence, subgroup by risk of bias: allocation concealment. Review:


pylori eradication



Study or subgroup

14 days

10 days


Weight


n/N

n/N


2/57

20/118

3.5 %

0.21 [ 0.05, 0.86 ]

Subtotal (95% CI)

57

118

3.5 %

0.21 [ 0.05, 0.86 ]

1 Low risk

Total events: 2 (14 days), 20 (10 days) Heterogeneity: not applicable Test for overall effect: Z = 2.18 (P = 0.030) 2 Unclear risk Laine 1996

4/50

5/50

4.4 %

0.80 [ 0.23, 2.81 ]

Katicic 1997

9/52

13/58

10.0 %

0.77 [ 0.36, 1.66 ]

Fennerty 1998

33/136

38/148

21.5 %

0.95 [ 0.63, 1.42 ]

Mantzaris 1999

10/55

17/78

11.3 %

0.83 [ 0.41, 1.68 ]

12/138

23/116

12.5 %

0.44 [ 0.23, 0.84 ]

7/87

17/86

8.8 %

0.41 [ 0.18, 0.93 ]

Palmas 2002

18/64

10/42

12.1 %

1.18 [ 0.61, 2.30 ]

Park 2009a

4/29

5/27

4.7 %

0.74 [ 0.22, 2.49 ]

10/102

20/103

11.1 %

0.50 [ 0.25, 1.02 ]

713

708

96.5 %

0.73 [ 0.57, 0.94 ]

100.0 %

0.69 [ 0.52, 0.91 ]

Kang 2000a Cho 2001

Karatapanis 2011

Subtotal (95% CI)


Total (95% CI)

770

826


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days


253

Analysis 6.5. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 5 H. pylori persistence, subgroup by risk of bias: overall. Review:


pylori eradication



Study or subgroup

14 days

10 days


Weight


n/N

n/N

Mantzaris 1999

10/55

17/78

11.3 %

0.83 [ 0.41, 1.68 ]

Palmas 2002

18/64

10/42

12.1 %

1.18 [ 0.61, 2.30 ]

10/102

20/103

11.1 %

0.50 [ 0.25, 1.02 ]

221

223

34.5 %

0.80 [ 0.49, 1.30 ]

1 High risk

Karatapanis 2011

Subtotal (95% CI)

Total events: 38 (14 days), 47 (10 days) Heterogeneity: Tau2 = 0.06; Chi2 = 2.96, df = 2 (P = 0.23); I2 =33% Test for overall effect: Z = 0.89 (P = 0.37) 2 Unclear risk Laine 1996

4/50

5/50

4.4 %

0.80 [ 0.23, 2.81 ]

Katicic 1997

9/52

13/58

10.0 %

0.77 [ 0.36, 1.66 ]

Fennerty 1998

33/136

38/148

21.5 %

0.95 [ 0.63, 1.42 ]

Kang 2000a

12/138

23/116

12.5 %

0.44 [ 0.23, 0.84 ]

Cho 2001

7/87

17/86

8.8 %

0.41 [ 0.18, 0.93 ]


2/57

20/118

3.5 %

0.21 [ 0.05, 0.86 ]

Park 2009a

4/29

5/27

4.7 %

0.74 [ 0.22, 2.49 ]

549

603

65.5 %

0.62 [ 0.43, 0.90 ]

100.0 %

0.69 [ 0.52, 0.91 ]

Subtotal (95% CI)


Total (95% CI)

770

826


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days


254

Analysis 6.6. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 6 Patients with adverse events. Review:


pylori eradication

Comparison: 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses Outcome: 6 Patients with adverse events

Study or subgroup

14 days

10 days


Weight


n/N

n/N

14/50

13/50

14.6 %

1.08 [ 0.56, 2.05 ]

Fennerty 1998

46/136

56/148

62.0 %

0.89 [ 0.65, 1.22 ]

Mantzaris 1999

6/49

7/69

5.8 %

1.21 [ 0.43, 3.37 ]

20/87

16/86

17.7 %

1.24 [ 0.69, 2.22 ]

322

353

100.0 %

0.99 [ 0.77, 1.27 ]

Laine 1996

Cho 2001

Total (95% CI)


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days


255

Analysis 6.7. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 7 Patients discontinued treatment due to adverse events. Review:


pylori eradication

Comparison: 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses Outcome: 7 Patients discontinued treatment due to adverse events Study or subgroup

14 days

10 days


Weight


n/N

n/N

2/50

5/50

30.7 %

0.40 [ 0.08, 1.97 ]

6/136

3/148

41.0 %

2.18 [ 0.56, 8.53 ]


1/57

5/118

17.7 %

0.41 [ 0.05, 3.46 ]

Park 2009a

0/29

0/27

Karatapanis 2011

1/102

1/103

10.6 %

1.01 [ 0.06, 15.93 ]

Total (95% CI)

374

446

100.0 %

0.89 [ 0.36, 2.20 ]

Laine 1996 Fennerty 1998

Not estimable


0.01

0.1

Favours 14 days

1

10

100

Favours 10 days


256

Analysis 6.8. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 8 Adverse event: Nausea/Vomiting. Review:


pylori eradication

Comparison: 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses Outcome: 8 Adverse event: Nausea/Vomiting

Study or subgroup

14 days

10 days

n/N

n/N

Cho 2001

5/87

4/86

56.6 %

1.24 [ 0.34, 4.45 ]


3/57

4/118

43.4 %

1.55 [ 0.36, 6.71 ]

144

204

100.0 %

1.36 [ 0.52, 3.58 ]

Total (95% CI)


Weight



0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days


257

Analysis 6.9. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 9 Adverse event: Diarrhoea. Review:


pylori eradication

Comparison: 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses Outcome: 9 Adverse event: Diarrhoea

Study or subgroup

14 days

10 days


Weight


n/N

n/N

Cho 2001

5/87

5/86

63.0 %

0.99 [ 0.30, 3.29 ]


2/57

6/118

37.0 %

0.69 [ 0.14, 3.31 ]

144

204

100.0 %

0.87 [ 0.33, 2.25 ]

Total (95% CI)


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days


258

Analysis 6.10. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 10 Adverse event: Taste disturbance or glossitis. Review:


pylori eradication

Comparison: 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses Outcome: 10 Adverse event: Taste disturbance or glossitis

Study or subgroup

14 days

10 days

n/N

n/N

Cho 2001

5/87

6/86

53.2 %

0.82 [ 0.26, 2.60 ]


4/57

6/118

46.8 %

1.38 [ 0.41, 4.70 ]

144

204

100.0 %

1.05 [ 0.45, 2.42 ]

Total (95% CI)


Weight



0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days

Analysis 6.11. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 11 Adverse event: Headache. Review:


pylori eradication

Comparison: 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses Outcome: 11 Adverse event: Headache

Study or subgroup


14 days

10 days

n/N

n/N

3/57

4/118



0.1 0.2

0.5

Favours 14 days


1

2

5

10

Favours 10 days

259

Analysis 6.12. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 12 Adverse event: Loss of appetite. Review:


pylori eradication

Comparison: 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses Outcome: 12 Adverse event: Loss of appetite

Study or subgroup


14 days

10 days

n/N

n/N

1/57

3/118



0.1 0.2

0.5

1

Favours 14 days

2

5

10

Favours 10 days

Analysis 6.13. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 13 Adverse event: Abdominal pain. Review:


pylori eradication

Comparison: 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses Outcome: 13 Adverse event: Abdominal pain

Study or subgroup


14 days

10 days

n/N

n/N

2/57

3/118



0.1 0.2

0.5

Favours 14 days


1

2

5

10

Favours 10 days

260

Analysis 6.14. Comparison 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses, Outcome 14 Adverse event: Skin rash or itching. Review:


pylori eradication

Comparison: 6 PPI + clarithromycin + amoxicillin triple therapy,14 days versus 10 days, subgroup and AE analyses Outcome: 14 Adverse event: Skin rash or itching

Study or subgroup

Cho 2001

14 days

10 days

n/N

n/N

2/87

1/86



0.01

0.1

Favours 14 days

1

10

100

Favours 10 days

Analysis 7.1. Comparison 7 PPI + clarithromycin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimen. Review:


pylori eradication

Comparison: 7 PPI + clarithromycin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 1 H.


Study or subgroup

14 days

7 days

n/N

n/N


Weight


1 PPI (lansoprazole or omeprazole) and two antibiotics used twice daily at standard doses Paoluzi 1998

10/48

18/54

9.6 %

0.63 [ 0.32, 1.22 ]

Paoluzi 2006

53/121

59/122

57.8 %

0.91 [ 0.69, 1.19 ]

169

176

67.4 %

0.85 [ 0.66, 1.12 ]


Heterogeneity: Tau2 = 0.00; Chi2 = 1.04, df = 1 (P = 0.31); I2 =4% Test for overall effect: Z = 1.15 (P = 0.25) 2 pantoprazole 40mg bid+clarithromycin 500mg bid+ metronidazole 500mg bid used only 10 days in the 14 days group Dammann 2000

Subtotal (95% CI)

31/123

32/121

23.8 %

0.95 [ 0.62, 1.46 ]

123

121

23.8 %

0.95 [ 0.62, 1.46 ]

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days

(Continued . . . )


261


14 days

7 days

n/N

n/N


Weight


Total events: 31 (14 days), 32 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 0.22 (P = 0.82) 3 omeprazole 20mg bid+ clarithromycin 250mg bid + metronidazole 250mg qid Dal Bo’ 1998

8/33

21/66

8.8 %

0.76 [ 0.38, 1.53 ]

33

66

8.8 %

0.76 [ 0.38, 1.53 ]

363

100.0 %

0.87 [ 0.71, 1.07 ]



Total (95% CI)

325


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


262

Analysis 7.2. Comparison 7 PPI + clarithromycin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 2 H. pyloris persistence, subgroup by location. Review:


pylori eradication


pyloris persistence, subgroup by location

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Paoluzi 1998

10/48

18/54

9.6 %

0.63 [ 0.32, 1.22 ]

Dal Bo’ 1998

8/33

21/66

8.8 %

0.76 [ 0.38, 1.53 ]

Dammann 2000

31/123

32/121

23.8 %

0.95 [ 0.62, 1.46 ]

Paoluzi 2006

53/121

59/122

57.8 %

0.91 [ 0.69, 1.19 ]

325

363

100.0 %

0.87 [ 0.71, 1.07 ]

1 Eruopean countries

Total (95% CI)


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


263

Analysis 7.3. Comparison 7 PPI + clarithromycin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 3 H. pyloris persistence, subgroup by baseline PUD or FD. Review:


pylori eradication


pyloris persistence, subgroup by baseline PUD or FD

Study or subgroup

14 days

7 days


Weight


n/N

n/N

31/123

32/121

23.8 %

0.95 [ 0.62, 1.46 ]

123

121

23.8 %

0.95 [ 0.62, 1.46 ]

1 PUD patients Dammann 2000


Test for overall effect: Z = 0.22 (P = 0.82) 2 FD patients Dal Bo’ 1998

8/33

21/66

8.8 %

0.76 [ 0.38, 1.53 ]

Paoluzi 1998

10/48

18/54

9.6 %

0.63 [ 0.32, 1.22 ]

81

120

18.4 %

0.69 [ 0.42, 1.11 ]


Heterogeneity: Tau2 = 0.0; Chi2 = 0.16, df = 1 (P = 0.69); I2 =0.0% Test for overall effect: Z = 1.52 (P = 0.13) 3 Mixed PUD and FD patients Paoluzi 2006

53/121

59/122

57.8 %

0.91 [ 0.69, 1.19 ]

121

122

57.8 %

0.91 [ 0.69, 1.19 ]

363

100.0 %

0.87 [ 0.71, 1.07 ]



Total (95% CI)

325


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


264

Analysis 7.4. Comparison 7 PPI + clarithromycin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 4 H. pyloris persistence, subgroup by risk of bias: overall. Review:


pylori eradication


pyloris persistence, subgroup by risk of bias: overall

Study or subgroup

14 days

7 days


Weight


n/N

n/N

10/48

18/54

9.6 %

0.63 [ 0.32, 1.22 ]

48

54

9.6 %

0.63 [ 0.32, 1.22 ]

8/33

21/66

8.8 %

0.76 [ 0.38, 1.53 ]

Dammann 2000

31/123

32/121

23.8 %

0.95 [ 0.62, 1.46 ]

Paoluzi 2006

53/121

59/122

57.8 %

0.91 [ 0.69, 1.19 ]

277

309

90.4 %

0.90 [ 0.73, 1.12 ]

100.0 %

0.87 [ 0.71, 1.07 ]

1 Unclear risk Paoluzi 1998


Test for overall effect: Z = 1.38 (P = 0.17) 2 High risk Dal Bo’ 1998



Total (95% CI)

325

363


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


265

Analysis 7.5. Comparison 7 PPI + clarithromycin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 5 Patients with adverse events. Review:


pylori eradication

Comparison: 7 PPI + clarithromycin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 5 Patients with adverse events

Study or subgroup

Dal Bo’ 1998 Dammann 2000

Total (95% CI)

14 days

7 days


Weight


n/N

n/N

3/33

5/66

8.6 %

1.20 [ 0.31, 4.72 ]

32/123

32/121

91.4 %

0.98 [ 0.65, 1.50 ]

156

187

100.0 %

1.00 [ 0.67, 1.50 ]


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


266

Analysis 7.6. Comparison 7 PPI + clarithromycin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 6 Patients discontinuing treatment due to adverse events. Review:


pylori eradication

Comparison: 7 PPI + clarithromycin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 6 Patients discontinuing treatment due to adverse events

Study or subgroup

14 days

7 days

n/N

n/N

Dal Bo’ 1998

0/33

0/66

Paoluzi 2006

7/109

8/115

100.0 %

0.92 [ 0.35, 2.46 ]

142

181

100.0 %

0.92 [ 0.35, 2.46 ]

Total (95% CI)


Weight

Risk Ratio MH,Random,95% CI Not estimable

Total events: 7 (14 days), 8 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 0.16 (P = 0.87) Test for subgroup differences: Not applicable

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


267

Analysis 8.1. Comparison 8 PPI + clarithromycin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimen. Review:


pylori eradication



Study or subgroup

10 days

7 days

n/N

n/N


Weight


1 Rabeprazole 20mg bid +clarithromycin 500mg bid + tinidazole 500mg bid Di Mario 2003a

Subtotal (95% CI)

14/47

15/52

93.6 %

1.03 [ 0.56, 1.90 ]

47

52

93.6 %

1.03 [ 0.56, 1.90 ]

Total events: 14 (10 days), 15 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 0.10 (P = 0.92) 2 Omeprazole 20mg bid+ clarithromycin 250mg bid+ metronidazole 400mg bid Hurenkamp 2000

1/24

2/25

6.4 %

0.52 [ 0.05, 5.38 ]

Subtotal (95% CI)

24

25

6.4 %

0.52 [ 0.05, 5.38 ]

77

100.0 %

0.99 [ 0.55, 1.79 ]


Total (95% CI)

71


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


268

Analysis 8.2. Comparison 8 PPI + clarithromycin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 2 Patients with adverse events. Review:


pylori eradication

Comparison: 8 PPI + clarithromycin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 2 Patients with adverse events

Study or subgroup

Di Mario 2003a

10 days

7 days

n/N

n/N

12/47

9/52

100.0 %

1.48 [ 0.68, 3.18 ]

47

52

100.0 %

1.48 [ 0.68, 3.18 ]

Total (95% CI)


Weight



0.1 0.2

0.5

1

Favours 10 days

2

5

10

Favours 7 days

Analysis 8.3. Comparison 8 PPI + clarithromycin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 3 Patients discontined treatment due to adverse events. Review:


pylori eradication

Comparison: 8 PPI + clarithromycin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 3 Patients discontined treatment due to adverse events

Study or subgroup

10 days

7 days

n/N

n/N

Hurenkamp 2000

0/24

0/25

Di Mario 2003a

3/47

1/52

100.0 %

3.32 [ 0.36, 30.82 ]

71

77

100.0 %

3.32 [ 0.36, 30.82 ]

Total (95% CI)


Weight

Risk Ratio MH,Random,95% CI Not estimable


0.01

0.1

Favours 10 days

1

10

100

Favours 7 days


269

Analysis 9.1. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimen. Review:


pylori eradication

Comparison: 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 1 H.


Study or subgroup

14 days

7 days

n/N

n/N


Weight


1 PPI, amoxicillin used twice daily at standard doses, metronidazole 400mg bid Hu 1999

4/25

6/21

4.4 %

0.56 [ 0.18, 1.72 ]

Cui 2002

9/72

11/75

8.3 %

0.85 [ 0.38, 1.93 ]

Hu 2003

7/39

6/26

5.9 %

0.78 [ 0.29, 2.05 ]

Hu 2004

7/44

15/44

8.9 %

0.47 [ 0.21, 1.03 ]

180

166

27.5 %

0.64 [ 0.41, 1.01 ]


Heterogeneity: Tau2 = 0.0; Chi2 = 1.29, df = 3 (P = 0.73); I2 =0.0% Test for overall effect: Z = 1.92 (P = 0.055) 2 PPI, amoxicillin used twice daily at standard doses, metronidazole 500mg bid Katicic 1997

15/62

25/60

19.7 %

0.58 [ 0.34, 0.99 ]

Wong 2000

14/82

16/71

13.5 %

0.76 [ 0.40, 1.44 ]

Pellicano 2002

14/53

14/53

13.8 %

1.00 [ 0.53, 1.89 ]


4/58

32/122

5.7 %

0.26 [ 0.10, 0.71 ]

Subtotal (95% CI)

255

306

52.7 %

0.64 [ 0.40, 1.01 ]

Total events: 47 (14 days), 87 (7 days) Heterogeneity: Tau2 = 0.10; Chi2 = 5.55, df = 3 (P = 0.14); I2 =46% Test for overall effect: Z = 1.93 (P = 0.054) 3 PPI, amoxicillin used twice daily at standard doses, metronidazole 250mg qid Berrutti 2008

Subtotal (95% CI)

9/34

7/30

7.6 %

1.13 [ 0.48, 2.67 ]

34

30

7.6 %

1.13 [ 0.48, 2.67 ]

Total events: 9 (14 days), 7 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 0.29 (P = 0.77) 4 PPI, amoxicillin used twice daily at standard doses, tinidazole 500mg bid

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days

(Continued . . . )


270


14 days

7 days


Weight


n/N

n/N

Chaudhary 2004

4/20

11/21

6.0 %

0.38 [ 0.15, 1.00 ]

Berrutti 2008

6/27

7/27

6.2 %

0.86 [ 0.33, 2.22 ]

47

48

12.2 %

0.57 [ 0.26, 1.27 ]

100.0 %

0.67 [ 0.53, 0.85 ]



Total (95% CI)

516

550


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


271

Analysis 9.2. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 2 H. pylori persistence subgroup by location. Review:


pylori eradication


pylori persistence subgroup by location

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Katicic 1997

15/62

25/60

18.7 %

0.58 [ 0.34, 0.99 ]

Pellicano 2002

14/53

14/53

13.6 %

1.00 [ 0.53, 1.89 ]

Berrutti 2008

15/61

14/57

13.8 %

1.00 [ 0.53, 1.88 ]


4/58

32/122

5.9 %

0.26 [ 0.10, 0.71 ]

Subtotal (95% CI)

234

292

52.0 %

0.68 [ 0.41, 1.13 ]

1 European countries

Total events: 48 (14 days), 85 (7 days) Heterogeneity: Tau2 = 0.15; Chi2 = 6.90, df = 3 (P = 0.08); I2 =57% Test for overall effect: Z = 1.49 (P = 0.14) 2 Asian countries Hu 1999

4/25

6/21

4.7 %

0.56 [ 0.18, 1.72 ]

14/82

16/71

13.4 %

0.76 [ 0.40, 1.44 ]

Cui 2002

9/72

11/75

8.5 %

0.85 [ 0.38, 1.93 ]

Hu 2003

7/39

6/26

6.2 %

0.78 [ 0.29, 2.05 ]

Chaudhary 2004

4/20

11/21

6.2 %

0.38 [ 0.15, 1.00 ]

Hu 2004

7/44

15/44

9.0 %

0.47 [ 0.21, 1.03 ]

282

258

48.0 %

0.63 [ 0.45, 0.89 ]

100.0 %

0.67 [ 0.52, 0.86 ]

Wong 2000



Total (95% CI)

516

550


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


272

Analysis 9.3. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 3 H. pylori persistence, subgroup by baseline PUD or FD. Review:


pylori eradication



Study or subgroup

14 days

7 days


Weight


n/N

n/N

4/25

6/21

4.7 %

0.56 [ 0.18, 1.72 ]

Wong 2000

14/82

16/71

13.4 %

0.76 [ 0.40, 1.44 ]

Pellicano 2002

14/53

14/53

13.6 %

1.00 [ 0.53, 1.89 ]

Hu 2004

7/44

15/44

9.0 %

0.47 [ 0.21, 1.03 ]

Chaudhary 2004

4/20

11/21

6.2 %

0.38 [ 0.15, 1.00 ]

224

210

46.9 %

0.67 [ 0.47, 0.94 ]

1 PUD patients Hu 1999


Heterogeneity: Tau2 = 0.0; Chi2 = 3.87, df = 4 (P = 0.42); I2 =0.0% Test for overall effect: Z = 2.29 (P = 0.022) 2 FD patients Cui 2002

Subtotal (95% CI)

9/72

11/75

8.5 %

0.85 [ 0.38, 1.93 ]

72

75

8.5 %

0.85 [ 0.38, 1.93 ]

Total events: 9 (14 days), 11 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 0.38 (P = 0.70) 3 Mixed PUD and FD, or without specifying the baseline disease 15/62

25/60

18.7 %

0.58 [ 0.34, 0.99 ]

7/39

6/26

6.2 %

0.78 [ 0.29, 2.05 ]

15/61

14/57

13.8 %

1.00 [ 0.53, 1.88 ]


4/58

32/122

5.9 %

0.26 [ 0.10, 0.71 ]

Subtotal (95% CI)

220

265

44.5 %

0.63 [ 0.38, 1.04 ]

100.0 %

0.67 [ 0.52, 0.86 ]

Katicic 1997 Hu 2003 Berrutti 2008


Total (95% CI)

516

550


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


273

Analysis 9.4. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 4 H. pylori persistence subgroup by risk of bias: allocation concealment. Review:


pylori eradication


pylori persistence subgroup by risk of bias: allocation concealment

Study or subgroup

14 days

7 days


Weight


n/N

n/N

15/61

14/57

13.8 %

1.00 [ 0.53, 1.88 ]


4/58

32/122

5.9 %

0.26 [ 0.10, 0.71 ]

Subtotal (95% CI)

119

179

19.7 %

0.54 [ 0.14, 2.11 ]

1 Low risk Berrutti 2008

Total events: 19 (14 days), 46 (7 days) Heterogeneity: Tau2 = 0.79; Chi2 = 5.41, df = 1 (P = 0.02); I2 =82% Test for overall effect: Z = 0.88 (P = 0.38) 2 Unclear risk 15/62

25/60

18.7 %

0.58 [ 0.34, 0.99 ]

4/25

6/21

4.7 %

0.56 [ 0.18, 1.72 ]

Wong 2000

14/82

16/71

13.4 %

0.76 [ 0.40, 1.44 ]

Pellicano 2002

14/53

14/53

13.6 %

1.00 [ 0.53, 1.89 ]

Cui 2002

9/72

11/75

8.5 %

0.85 [ 0.38, 1.93 ]

Hu 2003

7/39

6/26

6.2 %

0.78 [ 0.29, 2.05 ]

Chaudhary 2004

4/20

11/21

6.2 %

0.38 [ 0.15, 1.00 ]

Hu 2004

7/44

15/44

9.0 %

0.47 [ 0.21, 1.03 ]

397

371

80.3 %

0.67 [ 0.51, 0.87 ]

100.0 %

0.67 [ 0.52, 0.86 ]

Katicic 1997 Hu 1999



Total (95% CI)

516

550


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


274

Analysis 9.5. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 5 H. pylori persistence subgroup by risk of bias: overall. Review:


pylori eradication


pylori persistence subgroup by risk of bias: overall

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Hu 1999

4/25

6/21

4.7 %

0.56 [ 0.18, 1.72 ]

Cui 2002

9/72

11/75

8.5 %

0.85 [ 0.38, 1.93 ]

14/53

14/53

13.6 %

1.00 [ 0.53, 1.89 ]

Hu 2003

7/39

6/26

6.2 %

0.78 [ 0.29, 2.05 ]

Chaudhary 2004

4/20

11/21

6.2 %

0.38 [ 0.15, 1.00 ]

15/61

14/57

13.8 %

1.00 [ 0.53, 1.88 ]

270

253

53.0 %

0.81 [ 0.58, 1.12 ]

1 High risk

Pellicano 2002

Berrutti 2008


Heterogeneity: Tau2 = 0.0; Chi2 = 3.62, df = 5 (P = 0.61); I2 =0.0% Test for overall effect: Z = 1.27 (P = 0.20) 2 Unclear risk Katicic 1997

15/62

25/60

18.7 %

0.58 [ 0.34, 0.99 ]

Wong 2000

14/82

16/71

13.4 %

0.76 [ 0.40, 1.44 ]

Hu 2004

7/44

15/44

9.0 %

0.47 [ 0.21, 1.03 ]


4/58

32/122

5.9 %

0.26 [ 0.10, 0.71 ]

Subtotal (95% CI)

246

297

47.0 %

0.54 [ 0.37, 0.78 ]

100.0 %

0.67 [ 0.52, 0.86 ]


Total (95% CI)

516

550


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


275

Analysis 9.6. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 6 Patients with adverse events. Review:


pylori eradication

Comparison: 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 6 Patients with adverse events

Study or subgroup

14 days

7 days


Weight


n/N

n/N

9/25

2/21

21.0 %

3.78 [ 0.92, 15.61 ]

11/82

8/71

42.6 %

1.19 [ 0.51, 2.80 ]

Hu 2004

6/43

5/43

30.4 %

1.20 [ 0.40, 3.64 ]

Berrutti 2008

5/61

0/57

6.0 %

10.29 [ 0.58, 182.01 ]

Total (95% CI)

211

192

100.0 %

1.73 [ 0.84, 3.58 ]

Hu 1999 Wong 2000


0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


276

Analysis 9.7. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 7 Patients discontinuing treatment due to adverse events. Review:


pylori eradication

Comparison: 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 7 Patients discontinuing treatment due to adverse events

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Hu 1999

0/25

0/21

Not estimable

Wong 2000

0/82

0/71

Not estimable

Pellicano 2002

3/53

0/53

Hu 2003

0/39

0/26

Not estimable

Chaudhary 2004

0/20

0/21

Not estimable

Hu 2004

0/43

0/43

Not estimable

Berrutti 2008

2/61

0/57

26.8 %

4.68 [ 0.23, 95.39 ]


1/58

4/122

45.2 %

0.53 [ 0.06, 4.60 ]

381

414

100.0 %

1.95 [ 0.36, 10.65 ]

Total (95% CI)

28.0 %

7.00 [ 0.37, 132.29 ]


0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


277

Analysis 9.8. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 8 Adverse events: Diarrhoea. Review:


pylori eradication

Comparison: 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 8 Adverse events: Diarrhoea

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Wong 2000

0/82

1/71

13.5 %

0.29 [ 0.01, 6.99 ]

Chaudhary 2004

1/20

1/21

18.7 %

1.05 [ 0.07, 15.68 ]

Berrutti 2008

2/61

0/57

15.0 %

4.68 [ 0.23, 95.39 ]


2/58

5/122

52.8 %

0.84 [ 0.17, 4.21 ]

221

271

100.0 %

0.98 [ 0.31, 3.16 ]



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


278

Analysis 9.9. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 9 Adverse event: Nausea/vomiting/epigastric discomfort. Review:


pylori eradication

Comparison: 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 9 Adverse event: Nausea/vomiting/epigastric discomfort

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Hu 1999

6/25

2/21

33.9 %

2.52 [ 0.57, 11.20 ]

Wong 2000

0/82

1/71

7.7 %

0.29 [ 0.01, 6.99 ]


4/58

10/122

58.3 %

0.84 [ 0.28, 2.57 ]

165

214

100.0 %

1.12 [ 0.46, 2.74 ]

Total (95% CI)


0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


279

Analysis 9.10. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 10 Adverse events: Metallic taste/dysgeusia/taste disturbance. Review:


pylori eradication

Comparison: 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 10 Adverse events: Metallic taste/dysgeusia/taste disturbance

Study or subgroup

14 days n/N

n/N

Chaudhary 2004

2/20

2/21

21.0 %

1.05 [ 0.16, 6.76 ]

Berrutti 2008

2/61

0/57

8.0 %

4.68 [ 0.23, 95.39 ]


6/58

8/122

71.0 %

1.58 [ 0.57, 4.34 ]

139

200

100.0 %

1.58 [ 0.67, 3.71 ]

Total (95% CI)

7 days


Weight



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


280

Analysis 9.11. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 11 Adverse event: Epigastric pain/abdominal pain. Review:


pylori eradication

Comparison: 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 11 Adverse event: Epigastric pain/abdominal pain

Study or subgroup

14 days

7 days

n/N

n/N

Wong 2000

3/82

3/71

46.6 %

0.87 [ 0.18, 4.16 ]


3/58

4/122

53.4 %

1.58 [ 0.36, 6.82 ]

140

193

100.0 %

1.19 [ 0.41, 3.48 ]

Total (95% CI)


Weight



0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


281

Analysis 9.12. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 12 Adverse event: Dizziness. Review:


pylori eradication

Comparison: 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 12 Adverse event: Dizziness

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Hu 1999

2/25

0/21

46.0 %

4.23 [ 0.21, 83.53 ]

Wong 2000

1/82

1/71

54.0 %

0.87 [ 0.06, 13.59 ]

107

92

100.0 %

1.80 [ 0.24, 13.59 ]



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


282

Analysis 9.13. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 13 Adverse events: Skin rush. Review:


pylori eradication

Comparison: 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 13 Adverse events: Skin rush

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Hu 1999

1/25

0/21

49.9 %

2.54 [ 0.11, 59.23 ]

Chaudhary 2004

0/20

1/21

50.1 %

0.35 [ 0.02, 8.10 ]

Total (95% CI)

45

42

100.0 %

0.94 [ 0.10, 8.70 ]


0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


283

Analysis 9.14. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 14 Adverse event: Headache. Review:


pylori eradication

Comparison: 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 14 Adverse event: Headache

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Berrutti 2008

1/61

0/57

8.1 %

2.81 [ 0.12, 67.52 ]


6/58

11/122

91.9 %

1.15 [ 0.45, 2.95 ]

119

179

100.0 %

1.23 [ 0.50, 3.05 ]



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days

Analysis 9.15. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 15 Adverse event: Flatulence. Review:


pylori eradication

Comparison: 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 15 Adverse event: Flatulence

Study or subgroup

Wong 2000

14 days

7 days

n/N

n/N

3/82

2/71



0.1 0.2

0.5

Favours 14 days


1

2

5

10

Favours 7 days

284

Analysis 9.16. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 16 Adverse event: Malaise. Review:


pylori eradication

Comparison: 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 16 Adverse event: Malaise

Study or subgroup

Wong 2000

14 days

7 days

n/N

n/N

2/82

1/71



0.01

0.1

1

Favours 14 days

10

100

Favours 7 day

Analysis 9.17. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 17 Adverse event: Heartburn. Review:


pylori eradication

Comparison: 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 17 Adverse event: Heartburn

Study or subgroup

Wong 2000

14 days

7 days

n/N

n/N

1/82

1/71



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

285

Analysis 9.18. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 18 Advere event: Regurgitation. Review:


pylori eradication

Comparison: 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 18 Advere event: Regurgitation

Study or subgroup

14 days

7 days

n/N

n/N

1/82

0/71

Wong 2000



0.01

0.1

1

Favours 14 days

10

100

Favours 7 days

Analysis 9.19. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 19 Adverse event: Pruritus. Review:


pylori eradication

Comparison: 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 19 Adverse event: Pruritus

Study or subgroup

Wong 2000

14 days

7 days

n/N

n/N

1/82

0/71



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

286

Analysis 9.20. Comparison 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 20 Adverse event: Loss of appetite. Review:


pylori eradication

Comparison: 9 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 20 Adverse event: Loss of appetite

Study or subgroup

14 days

7 days

n/N

n/N

2/58

3/122




0.05

0.2

Favours 14 days

1

5

20

Favours 7 days



pylori eradication



Study or subgroup

10 days

7 days

n/N

n/N


Weight


1 PPI, amoxicillin twice daily at standard doses, metronidazole 500mg bid Katicic 1997

18/58

25/60

30.7 %

0.74 [ 0.46, 1.21 ]

Pellicano 2002

15/53

14/53

18.8 %

1.07 [ 0.58, 1.99 ]

24/117

32/122

33.6 %

0.78 [ 0.49, 1.24 ]

228

235

83.1 %

0.82 [ 0.61, 1.11 ]

8.8 %

1.11 [ 0.45, 2.76 ]



Heterogeneity: Tau2 = 0.0; Chi2 = 0.90, df = 2 (P = 0.64); I2 =0.0% Test for overall effect: Z = 1.28 (P = 0.20) 2 PPI, amoxicillin twice daily at standard doses, metronidazole 250mg qid Berrutti 2008

7/27

7/30 0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days

(Continued . . . )


287


10 days

7 days

n/N

n/N

27

30

Subtotal (95% CI)


Weight


8.8 %

1.11 [ 0.45, 2.76 ]

Total events: 7 (10 days), 7 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 0.23 (P = 0.82) 3 PPI, amoxicillin twice daily at standard doses, tinidazole 500mg bid Berrutti 2008

Subtotal (95% CI)

6/26

7/27

8.1 %

0.89 [ 0.34, 2.30 ]

26

27

8.1 %

0.89 [ 0.34, 2.30 ]

292

100.0 %

0.85 [ 0.65, 1.12 ]


Total (95% CI)

281


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


288



pylori eradication



Study or subgroup

10 days

7 days


Weight


n/N

n/N

Katicic 1997

18/58

25/60

30.7 %

0.74 [ 0.46, 1.21 ]

Pellicano 2002

15/53

14/53

18.8 %

1.07 [ 0.58, 1.99 ]

Berrutti 2008

13/53

14/57

16.9 %

1.00 [ 0.52, 1.92 ]

24/117

32/122

33.6 %

0.78 [ 0.49, 1.24 ]

281

292

100.0 %

0.85 [ 0.65, 1.12 ]



Total (95% CI)


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


289

Analysis 10.3. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 3 H. pylori persistence subgroup by baseline PUD or FD. Review:


pylori eradication


pylori persistence subgroup by baseline PUD or FD

Study or subgroup

10 days

7 days


Weight


n/N

n/N

15/53

14/53

18.8 %

1.07 [ 0.58, 1.99 ]

53

53

18.8 %

1.07 [ 0.58, 1.99 ]

1 PUD patients Pellicano 2002


Test for overall effect: Z = 0.22 (P = 0.83) 2 Mixed PUD and FD, or without specifying the baseline disease Katicic 1997

18/58

25/60

30.7 %

0.74 [ 0.46, 1.21 ]

Berrutti 2008

13/53

14/57

16.9 %

1.00 [ 0.52, 1.92 ]

24/117

32/122

33.6 %

0.78 [ 0.49, 1.24 ]

228

239

81.2 %

0.81 [ 0.60, 1.09 ]

100.0 %

0.85 [ 0.65, 1.12 ]




Total (95% CI)

281

292


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


290

Analysis 10.4. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 4 H. pylori persistence, subgroup by risk of bias: allocation concealment. Review:


pylori eradication



Study or subgroup

10 days

7 days


Weight


n/N

n/N

13/53

14/57

16.9 %

1.00 [ 0.52, 1.92 ]

24/117

32/122

33.6 %

0.78 [ 0.49, 1.24 ]

170

179

50.5 %

0.85 [ 0.58, 1.24 ]

1 Low risk Berrutti 2008 Filipec Kanizaj 2009


Heterogeneity: Tau2 = 0.0; Chi2 = 0.36, df = 1 (P = 0.55); I2 =0.0% Test for overall effect: Z = 0.85 (P = 0.40) 2 Unclear risk Katicic 1997

18/58

25/60

30.7 %

0.74 [ 0.46, 1.21 ]

Pellicano 2002

15/53

14/53

18.8 %

1.07 [ 0.58, 1.99 ]

111

113

49.5 %

0.86 [ 0.58, 1.25 ]

100.0 %

0.85 [ 0.65, 1.12 ]



Total (95% CI)

281

292


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


291

Analysis 10.5. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 5 H. pylori persistence, subgroup by risk of bias: overall. Review:


pylori eradication



Study or subgroup

10 days

7 days


Weight


n/N

n/N

Pellicano 2002

15/53

14/53

18.8 %

1.07 [ 0.58, 1.99 ]

Berrutti 2008

13/53

14/57

16.9 %

1.00 [ 0.52, 1.92 ]

106

110

35.7 %

1.04 [ 0.66, 1.63 ]

1 High risk


Heterogeneity: Tau2 = 0.0; Chi2 = 0.02, df = 1 (P = 0.88); I2 =0.0% Test for overall effect: Z = 0.16 (P = 0.88) 2 Unclear risk 18/58

25/60

30.7 %

0.74 [ 0.46, 1.21 ]

24/117

32/122

33.6 %

0.78 [ 0.49, 1.24 ]

175

182

64.3 %

0.76 [ 0.55, 1.07 ]

100.0 %

0.85 [ 0.65, 1.12 ]

Katicic 1997 Filipec Kanizaj 2009



Total (95% CI)

281

292


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


292



pylori eradication


Study or subgroup

10 days

7 days


Weight


n/N

n/N

Berrutti 2008

1/53

0/57

100.0 %

3.22 [ 0.13, 77.41 ]

Total (95% CI)

53

57

100.0 %

3.22 [ 0.13, 77.41 ]


0.01

0.1

1

10

Favours 14 days

100

Favours 10 days

Analysis 10.7. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 7 Patients discontinuing treatment due to adverse events. Review:


pylori eradication

Comparison: 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 7 Patients discontinuing treatment due to adverse events

Study or subgroup

10 days

7 days


Weight


n/N

n/N

Pellicano 2002

3/53

0/53

18.2 %

7.00 [ 0.37, 132.29 ]

Berrutti 2008

1/53

0/57

15.6 %

3.22 [ 0.13, 77.41 ]

3/117

4/122

66.2 %

0.78 [ 0.18, 3.42 ]

223

232

100.0 %

1.45 [ 0.41, 5.18 ]



Heterogeneity: Tau2 = 0.07; Chi2 = 2.09, df = 2 (P = 0.35); I2 =4% Test for overall effect: Z = 0.57 (P = 0.57) Test for subgroup differences: Not applicable

0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


293

Analysis 10.8. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 8 Adverse event: Nausea/Vomiting. Review:


pylori eradication

Comparison: 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 8 Adverse event: Nausea/Vomiting

Study or subgroup

10 days

7 days

n/N

n/N

1/53

0/57

6.2 %

3.22 [ 0.13, 77.41 ]

11/117

10/122

93.8 %

1.15 [ 0.51, 2.60 ]

170

179

100.0 %

1.22 [ 0.55, 2.70 ]

Berrutti 2008 Filipec Kanizaj 2009

Total (95% CI)


Weight



0.01

0.1

Favours 10 days

1

10

100

Favours 7 days


294

Analysis 10.9. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 9 Adverse event: Diarrhoea. Review:


pylori eradication

Comparison: 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 9 Adverse event: Diarrhoea

Study or subgroup


10 days

7 days

n/N

n/N

4/117

5/122



0.1 0.2

0.5

1

Favours 14 days

2

5

10

Favours 7 days

Analysis 10.10. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 10 Adverse event: Abdominal pain. Review:


pylori eradication

Comparison: 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 10 Adverse event: Abdominal pain

Study or subgroup


10 days

7 days

n/N

n/N

4/117

4/122



0.1 0.2

0.5

Favours experimental


1

2

5

10

Favours control

295



pylori eradication


Study or subgroup


10 days

7 days

n/N

n/N

3/117

3/122



0.1 0.2

0.5

1

Favours 10 days

2

5

10

Favours 7 days



pylori eradication


Study or subgroup


10 days

7 days

n/N

n/N

12/109

11/113



0.1 0.2

0.5

Favours 10 days


1

2

5

10

Favours 7 days

296

Analysis 10.13. Comparison 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 13 Adverse event: Taste disturbance. Review:


pylori eradication

Comparison: 10 PPI + amoxicillin + a nitroimidazole triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 13 Adverse event: Taste disturbance

Study or subgroup

10 days


7 days

n/N

n/N

8/117

8/122



0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days



pylori eradication



Study or subgroup

14 days

10 days

n/N

n/N


Weight


1 PPI and amoxicillin used twice daily at standard doses, metronidazole 500mg bid Katicic 1997

15/62

18/58

32.9 %

0.78 [ 0.43, 1.40 ]

Pellicano 2002

14/53

15/53

29.1 %

0.93 [ 0.50, 1.74 ]


4/58

24/117

11.0 %

0.34 [ 0.12, 0.92 ]

Subtotal (95% CI)

173

228

73.1 %

0.71 [ 0.43, 1.17 ]

15.6 %

1.02 [ 0.44, 2.39 ]

Total events: 33 (14 days), 57 (10 days) Heterogeneity: Tau2 = 0.07; Chi2 = 3.05, df = 2 (P = 0.22); I2 =35% Test for overall effect: Z = 1.34 (P = 0.18) 2 PPI and amoxicillin used twice daily at standard doses, metronidazole 250mg qid Berrutti 2008

9/34

7/27 0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days

(Continued . . . )


297


14 days

10 days

n/N

n/N

34

27

Subtotal (95% CI)


Weight


15.6 %

1.02 [ 0.44, 2.39 ]

Total events: 9 (14 days), 7 (10 days) Heterogeneity: not applicable Test for overall effect: Z = 0.05 (P = 0.96) 3 PPI and amoxicillin used twice daily at standard doses, tinidazole 500mg bid Berrutti 2008

Subtotal (95% CI)

6/27

6/26

11.3 %

0.96 [ 0.36, 2.61 ]

27

26

11.3 %

0.96 [ 0.36, 2.61 ]

281

100.0 %

0.80 [ 0.57, 1.12 ]


Total (95% CI)

234


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days


298



pylori eradication



Study or subgroup

10 days

7 days


Weight


n/N

n/N

Katicic 1997

15/62

18/58

31.6 %

0.78 [ 0.43, 1.40 ]

Pellicano 2002

14/53

15/53

28.8 %

0.93 [ 0.50, 1.74 ]

Berrutti 2008

15/61

13/53

27.1 %

1.00 [ 0.53, 1.91 ]

4/58

24/117

12.5 %

0.34 [ 0.12, 0.92 ]

234

281

100.0 %

0.79 [ 0.54, 1.15 ]



Total (95% CI)


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


299

Analysis 11.3. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 3 H. pylori persistence, subgroup by baseline PUD or FD. Review:


pylori eradication



Study or subgroup

14 days

10 days


Weight


n/N

n/N

14/53

15/53

28.8 %

0.93 [ 0.50, 1.74 ]

53

53

28.8 %

0.93 [ 0.50, 1.74 ]

1 PUD patients Pellicano 2002


Test for overall effect: Z = 0.22 (P = 0.83) 2 Mixed PUD and FD, or without specifying the baseline disease Katicic 1997

15/62

18/58

31.6 %

0.78 [ 0.43, 1.40 ]

Berrutti 2008

15/61

13/53

27.1 %

1.00 [ 0.53, 1.91 ]


4/58

24/117

12.5 %

0.34 [ 0.12, 0.92 ]

Subtotal (95% CI)

181

228

71.2 %

0.72 [ 0.42, 1.23 ]

100.0 %

0.79 [ 0.54, 1.15 ]


Total (95% CI)

234

281


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days


300

Analysis 11.4. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 4 H. pylori persistence, subgroup by risk of bias: allocation concealment. Review:


pylori eradication



Study or subgroup

10 days

7 days


Weight


n/N

n/N

15/61

13/53

27.1 %

1.00 [ 0.53, 1.91 ]


4/58

24/117

12.5 %

0.34 [ 0.12, 0.92 ]

Subtotal (95% CI)

119

170

39.6 %

0.62 [ 0.21, 1.86 ]

1 Low risk Berrutti 2008

Total events: 19 (10 days), 37 (7 days) Heterogeneity: Tau2 = 0.45; Chi2 = 3.38, df = 1 (P = 0.07); I2 =70% Test for overall effect: Z = 0.85 (P = 0.39) 2 Unclear risk Katicic 1997

15/62

18/58

31.6 %

0.78 [ 0.43, 1.40 ]

Pellicano 2002

14/53

15/53

28.8 %

0.93 [ 0.50, 1.74 ]

115

111

60.4 %

0.85 [ 0.55, 1.30 ]

100.0 %

0.79 [ 0.54, 1.15 ]



Total (95% CI)

234

281


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


301

Analysis 11.5. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 5 H. pylori persistence, subgroup by risk of bias: overall. Review:


pylori eradication



Study or subgroup

10 days

7 days


Weight


n/N

n/N

Pellicano 2002

14/53

15/53

28.8 %

0.93 [ 0.50, 1.74 ]

Berrutti 2008

15/61

13/53

27.1 %

1.00 [ 0.53, 1.91 ]

114

106

55.9 %

0.97 [ 0.62, 1.51 ]

1 High risk


Heterogeneity: Tau2 = 0.0; Chi2 = 0.02, df = 1 (P = 0.88); I2 =0.0% Test for overall effect: Z = 0.15 (P = 0.88) 2 Unclear risk 15/62

18/58

31.6 %

0.78 [ 0.43, 1.40 ]


4/58

24/117

12.5 %

0.34 [ 0.12, 0.92 ]

Subtotal (95% CI)

120

175

44.1 %

0.57 [ 0.25, 1.29 ]

100.0 %

0.79 [ 0.54, 1.15 ]

Katicic 1997


Total (95% CI)

234

281


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


302



pylori eradication


Study or subgroup

14 days

10 days


Weight


n/N

n/N

Berrutti 2008

5/61

1/53

100.0 %

4.34 [ 0.52, 36.02 ]

Total (95% CI)

61

53

100.0 %

4.34 [ 0.52, 36.02 ]


0.01

0.1

1

10

Favours 14 days

100

Favours 10 days

Analysis 11.7. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 7 Patients discontinuing treatment due to adverse event. Review:


pylori eradication

Comparison: 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses Outcome: 7 Patients discontinuing treatment due to adverse event

Study or subgroup

14 days

10 days


Weight


n/N

n/N

Pellicano 2002

3/53

3/53

52.3 %

1.00 [ 0.21, 4.73 ]

Berrutti 2008

2/61

1/53

22.5 %

1.74 [ 0.16, 18.63 ]


1/58

3/117

25.2 %

0.67 [ 0.07, 6.32 ]

172

223

100.0 %

1.02 [ 0.33, 3.15 ]



0.01

0.1

Favours 14 days

1

10

100

Favours 10 days


303

Analysis 11.8. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 8 Adverse event: Diarrhoea. Review:


pylori eradication

Comparison: 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses Outcome: 8 Adverse event: Diarrhoea

Study or subgroup

14 days

10 days


Weight


n/N

n/N

Berrutti 2008

2/61

0/53

23.4 %

4.35 [ 0.21, 88.73 ]


2/58

4/117

76.6 %

1.01 [ 0.19, 5.35 ]

119

170

100.0 %

1.42 [ 0.33, 6.12 ]



0.01

0.1

Favours 14 days

1

10

100

Favours 10 days


304

Analysis 11.9. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 9 Adverse event: Dysgeusia/taste disturbance. Review:


pylori eradication

Comparison: 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses Outcome: 9 Adverse event: Dysgeusia/taste disturbance

Study or subgroup

14 days

10 days

n/N

n/N

Berrutti 2008

2/61

0/53

10.1 %

4.35 [ 0.21, 88.73 ]


6/58

8/117

89.9 %

1.51 [ 0.55, 4.16 ]

119

170

100.0 %

1.68 [ 0.65, 4.39 ]

Total (95% CI)


Weight



0.01

0.1

Favours 14 days

1

10

100

Favours 10 days


305

Analysis 11.10. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 10 Adverse event: Nausea/Vomiting. Review:


pylori eradication

Comparison: 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses Outcome: 10 Adverse event: Nausea/Vomiting

Study or subgroup

14 days

10 days

n/N

n/N

Berrutti 2008

0/61

1/53

10.7 %

0.29 [ 0.01, 6.98 ]


4/58

11/117

89.3 %

0.73 [ 0.24, 2.20 ]

119

170

100.0 %

0.66 [ 0.23, 1.88 ]

Total (95% CI)


Weight



0.01

0.1

Favours 14 days

1

10

100

Favours 10 days


306



pylori eradication


Study or subgroup

14 days

10 days


Weight


n/N

n/N

Berrutti 2008

1/61

0/53

7.8 %

2.61 [ 0.11, 62.82 ]


6/58

12/117

92.2 %

1.01 [ 0.40, 2.55 ]

119

170

100.0 %

1.09 [ 0.45, 2.65 ]

Total (95% CI)


0.01

0.1

Favours 14 days

1

10

100

Favours 10 days



pylori eradication


Study or subgroup


14 days

10 days

n/N

n/N

2/58

3/117



0.1 0.2

0.5

Favours 14 days


1

2

5

10

Favours 10 days

307

Analysis 11.13. Comparison 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses, Outcome 13 Adverse event: Abdominal pain. Review:


pylori eradication

Comparison: 11 PPI + amoxicillin + a nitroimidazole triple therapy, 14 days versus 10 days, subgroup and AE analyses Outcome: 13 Adverse event: Abdominal pain

Study or subgroup

14 days

10 days

n/N

n/N

3/58

4/117




0.1 0.2

0.5

1

Favours 14 days

2

5

10

Favours 10 days

Analysis 12.1. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimens. Review:


pylori eradication

Comparison: 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 1 H.


Study or subgroup

14 days

7 days

n/N

n/N


Weight


1 Rabeprazole 20mg bid+amoxicillin 1g bid+ofloxacin 400mg bid Bosques-Padilla 2004

Subtotal (95% CI)

3/39

14/37

31.4 %

0.20 [ 0.06, 0.65 ]

39

37

31.4 %

0.20 [ 0.06, 0.65 ]

Total events: 3 (14 days), 14 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 2.68 (P = 0.0073) 2 Lansoprazole 30 mg bid + amoxicillin 1g bid + levofloxacin 500mg od Ercin 2010

Subtotal (95% CI)

14/40

37/51

68.6 %

0.48 [ 0.31, 0.76 ]

40

51

68.6 %

0.48 [ 0.31, 0.76 ]

Total events: 14 (14 days), 37 (7 days)

0.01

0.1

Favours 14 days

1

10

100

Favours 7 days

(Continued . . . )


308


14 days

7 days

n/N

n/N


Weight



Total (95% CI)

79

100.0 %

88

0.37 [ 0.16, 0.83 ]


0.01

0.1

1

Favours 14 days

10

100

Favours 7 days

Analysis 12.2. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 2 H. pylori persistence: subgroup by location. Review:


pylori eradication


pylori persistence: subgroup by location

Study or subgroup

14 days

7 days


Weight


n/N

n/N

14/40

37/51

68.6 %

0.48 [ 0.31, 0.76 ]

40

51

68.6 %

0.48 [ 0.31, 0.76 ]

3/39

14/37

31.4 %

0.20 [ 0.06, 0.65 ]

39

37

31.4 %

0.20 [ 0.06, 0.65 ]

1 Asian countries Ercin 2010


Test for overall effect: Z = 3.14 (P = 0.0017) 2 North Americian countries Bosques-Padilla 2004



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days

(Continued . . . )


309


14 days

7 days

n/N

n/N

79

88

Total (95% CI)


Weight

100.0 %


0.37 [ 0.16, 0.83 ]


0.01

0.1

1

Favours 14 days

10

100

Favours 7 days

Analysis 12.3. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 3 H. pylori persistence: subgroup by baseline PUD or FD. Review:


pylori eradication


pylori persistence: subgroup by baseline PUD or FD

Study or subgroup

14 days

7 days


Weight


n/N

n/N

14/40

37/51

68.6 %

0.48 [ 0.31, 0.76 ]

40

51

68.6 %

0.48 [ 0.31, 0.76 ]

3/39

14/37

31.4 %

0.20 [ 0.06, 0.65 ]

39

37

31.4 %

0.20 [ 0.06, 0.65 ]

88

100.0 %

0.37 [ 0.16, 0.83 ]

1 FD patients Ercin 2010


Test for overall effect: Z = 3.14 (P = 0.0017) 2 Mixed PUD and FD patients Bosques-Padilla 2004



Total (95% CI)

79


0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


310

Analysis 12.4. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 4 Patients discontinuing treatment due to adverse events. Review:


pylori eradication

Comparison: 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 4 Patients discontinuing treatment due to adverse events

Study or subgroup

14 days

7 days

n/N

n/N


1/39

1/37

50.1 %

0.95 [ 0.06, 14.62 ]

Ercin 2010

1/40

1/51

49.9 %

1.28 [ 0.08, 19.76 ]

79

88

100.0 %

1.10 [ 0.16, 7.62 ]

Total (95% CI)


Weight



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


311

Analysis 12.5. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 5 Adverse events: Diarrhoea. Review:


pylori eradication

Comparison: 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 5 Adverse events: Diarrhoea

Study or subgroup


14 days

7 days

n/N

n/N

1/39

3/37



0.01

0.1

1

Favours 14 days

10

100

Favours 7 days

Analysis 12.6. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 6 Adverse events: Headache. Review:


pylori eradication

Comparison: 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 6 Adverse events: Headache

Study or subgroup


14 days

7 days

n/N

n/N

1/39

4/37



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

312

Analysis 12.7. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 7 Adverse events: Skin rush or pruritus. Review:


pylori eradication

Comparison: 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 7 Adverse events: Skin rush or pruritus

Study or subgroup


14 days

7 days

n/N

n/N

1/39

1/37



0.01

0.1

1

10

Favours 14 days

100

Favours 7 days

Analysis 12.8. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 8 Adverse event: nausea/vomiting. Review:


pylori eradication

Comparison: 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 8 Adverse event: nausea/vomiting

Study or subgroup

Ercin 2010

14 days

7 days

n/N

n/N

1/40

0/51



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

313

Analysis 12.9. Comparison 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses, Outcome 9 Adverse event: Allergic reaction. Review:


pylori eradication

Comparison: 12 PPI + amoxicillin + a quinolone triple therapy, 14 days versus 7 days, subgroup and AE analyses Outcome: 9 Adverse event: Allergic reaction

Study or subgroup

14 days

7 days

n/N

n/N

0/40

1/51

Ercin 2010



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days

Analysis 13.1. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 1 H. pylori persistence, subgroup by regimens. Review:


pylori eradication



Study or subgroup

10 days

7 days

n/N

n/N


Weight


1 Lansoprazole 30mg bid + amoxicillin 1g bid+ moxifloxacin 200mg bid Bago 2010

Subtotal (95% CI)

12/75

18/75

55.6 %

0.67 [ 0.35, 1.29 ]

75

75

55.6 %

0.67 [ 0.35, 1.29 ]

Total events: 12 (10 days), 18 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 1.21 (P = 0.23) 2 Esomeprazole 20mg bid+ amoxicillin1g bid+ moxifloxacin 400mg bid Sacco 2010

Subtotal (95% CI)

9/94

20/102

44.4 %

0.49 [ 0.23, 1.02 ]

94

102

44.4 %

0.49 [ 0.23, 1.02 ]

Total events: 9 (10 days), 20 (7 days)

0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days

(Continued . . . )


314


10 days

7 days

n/N

n/N


Weight

Continued)



Total (95% CI)

169

100.0 %

177

0.58 [ 0.36, 0.95 ]


0.1 0.2

0.5

1

Favours 10 days

2

5

10

Favours 7 days

Analysis 13.2. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 2 H. pylori persistence subgroup by location. Review:


pylori eradication



Study or subgroup

10 days

7 days


Weight


n/N

n/N

Sacco 2010

9/94

20/102

44.4 %

0.49 [ 0.23, 1.02 ]

Bago 2010

12/75

18/75

55.6 %

0.67 [ 0.35, 1.29 ]

169

177

100.0 %

0.58 [ 0.36, 0.95 ]


Total (95% CI)


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


315

Analysis 13.3. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 3 H. pylori persistence subgroup by baseline PUD or FD. Review:


pylori eradication


pylori persistence subgroup by baseline PUD or FD

Study or subgroup

10 days

7 days


Weight


n/N

n/N

12/75

18/75

55.6 %

0.67 [ 0.35, 1.29 ]

75

75

55.6 %

0.67 [ 0.35, 1.29 ]

9/94

20/102

44.4 %

0.49 [ 0.23, 1.02 ]

94

102

44.4 %

0.49 [ 0.23, 1.02 ]

177

100.0 %

0.58 [ 0.36, 0.95 ]

1 FD patients Bago 2010


Test for overall effect: Z = 1.21 (P = 0.23) 2 Mixed PUD and FD patients Sacco 2010



Total (95% CI)

169


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


316

Analysis 13.4. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 4 Patients with adverse events. Review:


pylori eradication

Comparison: 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 4 Patients with adverse events

Study or subgroup

Bago 2010

10 days

7 days

n/N

n/N

18/75

11/75

100.0 %

1.64 [ 0.83, 3.22 ]

75

75

100.0 %

1.64 [ 0.83, 3.22 ]

Total (95% CI)


Weight



0.1 0.2

0.5

1

Favours 10 days

2

5

10

Favours 7 days

Analysis 13.5. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 5 Patients discontinuing treatment due to adverse events. Review:


pylori eradication

Comparison: 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 5 Patients discontinuing treatment due to adverse events

Study or subgroup

10 days

7 days

n/N

n/N

Bago 2010

3/75

2/75

76.6 %

1.50 [ 0.26, 8.72 ]

Sacco 2010

0/94

1/102

23.4 %

0.36 [ 0.01, 8.76 ]

169

177

100.0 %

1.08 [ 0.23, 5.02 ]

Total (95% CI)


Weight



0.01

0.1

Favours 10 days

1

10

100

Favours 7 days


317

Analysis 13.6. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 6 Adverse event: Epigastric discomfort/abdominal pain. Review:


pylori eradication

Comparison: 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 6 Adverse event: Epigastric discomfort/abdominal pain

Study or subgroup

10 days

7 days

n/N

n/N

Sacco 2010

1/90

1/97

22.0 %

1.08 [ 0.07, 16.98 ]

Bago 2010

4/75

3/75

78.0 %

1.33 [ 0.31, 5.75 ]

165

172

100.0 %

1.27 [ 0.35, 4.63 ]

Total (95% CI)


Weight



0.01

0.1

Favours 10 days

1

10

100

Favours 7 days


318

Analysis 13.7. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 7 Adverse event: Nausea or vomiting. Review:


pylori eradication

Comparison: 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 7 Adverse event: Nausea or vomiting

Study or subgroup

10 days

7 days

n/N

n/N

Bago 2010

3/75

2/75

37.2 %

1.50 [ 0.26, 8.72 ]

Sacco 2010

4/90

4/97

62.8 %

1.08 [ 0.28, 4.18 ]

165

172

100.0 %

1.22 [ 0.42, 3.57 ]

Total (95% CI)


Weight



0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


319

Analysis 13.8. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 8 Adverse event: Diarrrhoea. Review:


pylori eradication

Comparison: 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 8 Adverse event: Diarrrhoea

Study or subgroup

10 days

7 days


Weight


n/N

n/N

Bago 2010

5/75

3/75

65.9 %

1.67 [ 0.41, 6.73 ]

Sacco 2010

2/90

2/97

34.1 %

1.08 [ 0.16, 7.49 ]

165

172

100.0 %

1.44 [ 0.46, 4.46 ]



0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


320

Analysis 13.9. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 9 Adverse event: Metallic taste/taste disturbances. Review:


pylori eradication

Comparison: 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 9 Adverse event: Metallic taste/taste disturbances

Study or subgroup

10 days

7 days


Weight


n/N

n/N

Sacco 2010

0/90

1/97

48.0 %

0.36 [ 0.01, 8.70 ]

Bago 2010

2/75

0/75

52.0 %

5.00 [ 0.24, 102.42 ]

165

172

100.0 %

1.41 [ 0.11, 18.68 ]



0.001 0.01 0.1 Favours 10 days

1


Analysis 13.10. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 10 Adverse event: Constipation. Review:


pylori eradication

Comparison: 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 10 Adverse event: Constipation

Study or subgroup

Bago 2010

10 days

7 days

n/N

n/N

0/75

1/75



0.01

0.1

Favours 10 days


1

10

100

Favours 7 days

321

Analysis 13.11. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 11 Adverse event: Headache. Review:


pylori eradication

Comparison: 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 11 Adverse event: Headache

Study or subgroup

10 days

Bago 2010

7 days

n/N

n/N

2/75

1/75



0.01

0.1

1

Favours 10 days

10

100

Favours 7 days

Analysis 13.12. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 12 Adverse event: Pruritus. Review:


pylori eradication

Comparison: 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 12 Adverse event: Pruritus

Study or subgroup

Bago 2010

10 days

7 days

n/N

n/N

2/75

0/75



0.001 0.01 0.1 Favours 10 days


1


322

Analysis 13.13. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 13 Adverse event: Skin rash. Review:


pylori eradication

Comparison: 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 13 Adverse event: Skin rash

Study or subgroup

Bago 2010

10 days

7 days

n/N

n/N

0/75

1/75



0.01

0.1

1

Favours 10 days

10

100

Favours 7 days

Analysis 13.14. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 14 Adverse event: Aphthous stomatitis. Review:


pylori eradication

Comparison: 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 14 Adverse event: Aphthous stomatitis

Study or subgroup

Sacco 2010

10 days

7 days

n/N

n/N

0/90

2/97



0.01

0.1

Favours 10 days


1

10

100

Favours 7 days

323

Analysis 13.15. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 15 Adverse event: Bloating. Review:


pylori eradication

Comparison: 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 15 Adverse event: Bloating

Study or subgroup

Sacco 2010

10 days

7 days

n/N

n/N

2/90

3/97



0.1 0.2

0.5

1

Favours 10 days

2

5

10

Favours 7 days

Analysis 13.16. Comparison 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses, Outcome 16 Adverse event: loose stools. Review:


pylori eradication

Comparison: 13 PPI + amoxicillin + a quinolone triple therapy, 10 days versus 7 days, subgroup and AE analyses Outcome: 16 Adverse event: loose stools

Study or subgroup

Sacco 2010

10 days

7 days

n/N

n/N

2/90

3/97



0.1 0.2

0.5

Favours 10 days


1

2

5

10

Favours 7 days

324

Analysis 14.1. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 1 H. pylori persistence, subgroup by regimen. Review:


pylori eradication

Comparison: 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days Outcome: 1 H.


Study or subgroup

14 days

7 days

n/N

n/N


Weight


1 Omeprazole 20mg bid+ bismuth 240mg bid + tetracycline 750mg bid + metronidazole 500mg bid Emami 2006

Subtotal (95% CI)

14/23

18/23

44.7 %

0.78 [ 0.53, 1.15 ]

23

23

44.7 %

0.78 [ 0.53, 1.15 ]

Total events: 14 (14 days), 18 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 1.26 (P = 0.21) 2 Omeprazole 20mg bid + bismuth substrate 240mg bid + furazolidone 200mg bid+ amoxicillin 1g bid Daghaghzadeh 2007

Subtotal (95% CI)

21/78

22/78

37.2 %

0.95 [ 0.57, 1.59 ]

78

78

37.2 %

0.95 [ 0.57, 1.59 ]

Total events: 21 (14 days), 22 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 0.18 (P = 0.86) 3 Omeprazole 20mg bid +bismuth potassium citrate 220mg bid+ clarithromycin 500mg bid+ amoxicillin 1g bid Sun 2010

Subtotal (95% CI)

5/80

16/80

18.1 %

0.31 [ 0.12, 0.81 ]

80

80

18.1 %

0.31 [ 0.12, 0.81 ]

181

100.0 %

0.71 [ 0.44, 1.15 ]


Total (95% CI)

181


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


325

Analysis 14.2. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 2 H. pylori persistence, subgroup by location. Review:


pylori eradication



Study or subgroup

14 days

7 days


Weight


n/N

n/N

Emami 2006

14/23

18/23

44.7 %

0.78 [ 0.53, 1.15 ]

Daghaghzadeh 2007

21/78

22/78

37.2 %

0.95 [ 0.57, 1.59 ]

5/80

16/80

18.1 %

0.31 [ 0.12, 0.81 ]

181

181

100.0 %

0.71 [ 0.44, 1.15 ]

1 Asian countries

Sun 2010



0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


326

Analysis 14.3. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 3 H. pylori persistence, subgroup by baseline PUD or FD. Review:


pylori eradication



Study or subgroup

14 days

7 days


Weight


n/N

n/N

5/80

16/80

18.1 %

0.31 [ 0.12, 0.81 ]

80

80

18.1 %

0.31 [ 0.12, 0.81 ]

1 FD patients Sun 2010


Test for overall effect: Z = 2.39 (P = 0.017) 2 Mixed PUD or FD patients Emami 2006

14/23

18/23

44.7 %

0.78 [ 0.53, 1.15 ]

Daghaghzadeh 2007

21/78

22/78

37.2 %

0.95 [ 0.57, 1.59 ]

101

101

81.9 %

0.84 [ 0.62, 1.15 ]

100.0 %

0.71 [ 0.44, 1.15 ]



Total (95% CI)

181

181


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


327

Analysis 14.4. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 4 H. pylori persistence, subgroup by risk of bias: overall. Review:


pylori eradication



Study or subgroup

14 days

7 days


Weight


n/N

n/N

5/80

16/80

18.1 %

0.31 [ 0.12, 0.81 ]

80

80

18.1 %

0.31 [ 0.12, 0.81 ]

1 High risk Sun 2010


Test for overall effect: Z = 2.39 (P = 0.017) 2 Unclear risk Emami 2006

14/23

18/23

44.7 %

0.78 [ 0.53, 1.15 ]

Daghaghzadeh 2007

21/78

22/78

37.2 %

0.95 [ 0.57, 1.59 ]

101

101

81.9 %

0.84 [ 0.62, 1.15 ]

100.0 %

0.71 [ 0.44, 1.15 ]



Total (95% CI)

181

181


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


328

Analysis 14.5. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 5 Patients with adverse events. Review:


pylori eradication

Comparison: 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days Outcome: 5 Patients with adverse events

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Daghaghzadeh 2007

14/78

13/78

59.1 %

1.08 [ 0.54, 2.14 ]

Sun 2010

11/80

9/80

40.9 %

1.22 [ 0.54, 2.79 ]

158

158

100.0 %

1.13 [ 0.67, 1.92 ]



0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


329

Analysis 14.6. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 6 Patients discontinuing treatment due to adverse events. Review:


pylori eradication

Comparison: 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days Outcome: 6 Patients discontinuing treatment due to adverse events

Study or subgroup

14 days

7 days

n/N

n/N

Daghaghzadeh 2007

9/78

1/78

68.6 %

9.00 [ 1.17, 69.35 ]

Sun 2010

2/80

0/80

31.4 %

5.00 [ 0.24, 102.53 ]

158

158

100.0 %

7.48 [ 1.38, 40.63 ]

Total (95% CI)


Weight



0.001 0.01 0.1 Favours 14 days

1



330

Analysis 14.7. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 7 Adverse event: Diarrhoea. Review:


pylori eradication

Comparison: 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days Outcome: 7 Adverse event: Diarrhoea

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Daghaghzadeh 2007

3/78

1/78

17.9 %

3.00 [ 0.32, 28.22 ]

Sun 2010

7/80

6/80

82.1 %

1.17 [ 0.41, 3.32 ]

158

158

100.0 %

1.38 [ 0.54, 3.56 ]



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


331

Analysis 14.8. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 8 Adverse event: Skin rash/itching. Review:


pylori eradication

Comparison: 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days Outcome: 8 Adverse event: Skin rash/itching

Study or subgroup

14 days

7 days

n/N

n/N

Daghaghzadeh 2007

0/78

1/78

35.8 %

0.33 [ 0.01, 8.06 ]

Sun 2010

1/80

2/80

64.2 %

0.50 [ 0.05, 5.40 ]

158

158

100.0 %

0.43 [ 0.06, 2.91 ]

Total (95% CI)


Weight



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


332

Analysis 14.9. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 9 Adverse event: Dizziness/drowsiness. Review:


pylori eradication

Comparison: 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days Outcome: 9 Adverse event: Dizziness/drowsiness

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Daghaghzadeh 2007

4/78

3/78

40.2 %

1.33 [ 0.31, 5.76 ]

Sun 2010

5/80

5/80

59.8 %

1.00 [ 0.30, 3.32 ]

158

158

100.0 %

1.12 [ 0.44, 2.84 ]



0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days

Analysis 14.10. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 10 Adverse event: Abdominal discomfort. Review:


pylori eradication

Comparison: 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days Outcome: 10 Adverse event: Abdominal discomfort

Study or subgroup

Daghaghzadeh 2007

14 days

7 days

n/N

n/N

3/78

4/78



0.1 0.2

0.5

Favours 14 days


1

2

5

10

Favours 7 days

333

Analysis 14.11. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 11 Adverse event: Fever. Review:


pylori eradication

Comparison: 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days Outcome: 11 Adverse event: Fever

Study or subgroup

Daghaghzadeh 2007

14 ays

7 days

n/N

n/N

1/78

0/78



0.01

0.1

1

10

Favours 14 days

100

Favours 7 days

Analysis 14.12. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 12 Adverse event: Vomiting. Review:


pylori eradication

Comparison: 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days Outcome: 12 Adverse event: Vomiting

Study or subgroup

Daghaghzadeh 2007

14 days

7 days

n/N

n/N

1/78

2/78



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

334

Analysis 14.13. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 13 Adverse event: Fatigue. Review:


pylori eradication

Comparison: 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days Outcome: 13 Adverse event: Fatigue

Study or subgroup

Daghaghzadeh 2007

14 days

7 days

n/N

n/N

1/78

1/78



0.01

0.1

1

Favours 14 days

10

100

Favours 7 days

Analysis 14.14. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 14 Adverse event: Headache. Review:


pylori eradication

Comparison: 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days Outcome: 14 Adverse event: Headache

Study or subgroup

Daghaghzadeh 2007

14 days

7 days

n/N

n/N

7/78

1/78



0.01

0.1

Favours 14 days


1

10

100

Favours 17 days

335

Analysis 14.15. Comparison 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days, Outcome 15 Adverse event: Nausea. Review:


pylori eradication

Comparison: 14 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 7 days Outcome: 15 Adverse event: Nausea

Study or subgroup

14 days

Daghaghzadeh 2007

7 days

n/N

n/N

10/78

6/78



0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days

Analysis 15.1. Comparison 15 PPI + bismuth + two antibiotics quadruple therapy, 10 days versus 7 days, Outcome 1 H. pylori persistence, subgroup by regimens. Review:


pylori eradication



Study or subgroup

10 days

7 days

n/N

n/N


Weight


1 Pantoprazole 40mgbid+ colloidal bismuth subcitrate 220mgbid + metronidazole 400mgtid + tetracycline 750mgbid Zheng 2009

Subtotal (95% CI)

5/45

9/43

22.9 %

0.53 [ 0.19, 1.46 ]

45

43

22.9 %

0.53 [ 0.19, 1.46 ]

Total events: 5 (10 days), 9 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 1.23 (P = 0.22) 2 Rabeprazole 10mg bid+ bismuth 220mb bid+ amoxicillin 1g bid+ furazolidone 100mg bid Lv 2011

19/145

25/145

77.1 %

0.76 [ 0.44, 1.32 ]

145

145

77.1 %

0.76 [ 0.44, 1.32 ]


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days

(Continued . . . )


336


10 days

7 days

n/N

n/N


Weight



Total (95% CI)

190

100.0 %

188

0.70 [ 0.43, 1.14 ]


0.1 0.2

0.5

1

Favours 10 days

2

5

10

Favours 7 days

Analysis 15.2. Comparison 15 PPI + bismuth + two antibiotics quadruple therapy, 10 days versus 7 days, Outcome 2 H. pylori persistence, subgroup by location. Review:


pylori eradication



Study or subgroup

14 days

10 days


Weight


n/N

n/N

5/45

9/43

22.9 %

0.53 [ 0.19, 1.46 ]

19/145

25/145

77.1 %

0.76 [ 0.44, 1.32 ]

190

188

100.0 %

0.70 [ 0.43, 1.14 ]

1 Asian countries Zheng 2009 Lv 2011

Total (95% CI)


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days


337

Analysis 15.3. Comparison 15 PPI + bismuth + two antibiotics quadruple therapy, 10 days versus 7 days, Outcome 3 H. pylori persistence, subgroup by baseline disease. Review:


pylori eradication


pylori persistence, subgroup by baseline disease

Study or subgroup

14 days

7 days


Weight


n/N

n/N

5/45

9/43

22.9 %

0.53 [ 0.19, 1.46 ]

45

43

22.9 %

0.53 [ 0.19, 1.46 ]

19/145

25/145

77.1 %

0.76 [ 0.44, 1.32 ]

145

145

77.1 %

0.76 [ 0.44, 1.32 ]

188

100.0 %

0.70 [ 0.43, 1.14 ]

1 FD patients Zheng 2009


Test for overall effect: Z = 1.23 (P = 0.22) 2 PUD patients Lv 2011



Total (95% CI)

190


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days


338



pylori eradication


Study or subgroup

10 days

Zheng 2009

Total (95% CI)

7 days


Weight


n/N

n/N

1/45

1/43

100.0 %

0.96 [ 0.06, 14.80 ]

45

43

100.0 %

0.96 [ 0.06, 14.80 ]


0.01

0.1

1

10

Favours 10 days

100

Favours 7 days

Analysis 16.1. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 1 H. pylori persistence. Review:


pylori eradication


pylori persistence

Study or subgroup

14 days

10 days

n/N

n/N


Weight


1 PPI+ bismuth subcitrate 240mg + metronidazole 500mg + tetracycline 500mg BID Dore 2011

Total (95% CI)

17/202

16/215

100.0 %

1.13 [ 0.59, 2.18 ]

202

215

100.0 %

1.13 [ 0.59, 2.18 ]


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days


339

Analysis 16.2. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 2 Patients with adverse events. Review:


pylori eradication

Comparison: 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days Outcome: 2 Patients with adverse events

Study or subgroup

Dore 2011

Total (95% CI)

14 days

10 days


Weight


n/N

n/N

32/202

22/215

100.0 %

1.55 [ 0.93, 2.57 ]

202

215

100.0 %

1.55 [ 0.93, 2.57 ]


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days


340



pylori eradication


Study or subgroup

Dore 2011

Total (95% CI)

14 days

10 days


Weight


n/N

n/N

4/202

3/215

100.0 %

1.42 [ 0.32, 6.26 ]

202

215

100.0 %

1.42 [ 0.32, 6.26 ]


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days

Analysis 16.4. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 4 Adverse events: nausea. Review:


pylori eradication

Comparison: 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days Outcome: 4 Adverse events: nausea

Study or subgroup

14 days

10 days

n/N

n/N

Dore 2011

14/202

10/215



0.1 0.2

0.5

Favours 14 days


1

2

5

10

Favours 10 days

341

Analysis 16.5. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 5 Adverse events: vomiting. Review:


pylori eradication

Comparison: 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days Outcome: 5 Adverse events: vomiting

Study or subgroup

Dore 2011

14 days

10 days

n/N

n/N

3/202

0/215



0.001 0.01 0.1

1

Favours 14 days


Analysis 16.6. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 6 Adverse events: Stomach ache. Review:


pylori eradication

Comparison: 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days Outcome: 6 Adverse events: Stomach ache

Study or subgroup

Dore 2011

14 days

10 days

n/N

n/N

7/202

7/215



0.1 0.2

0.5

Favours 14 days


1

2

5

10

Favours 10 days

342

Analysis 16.7. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 7 Adverse events: diarrhoea. Review:


pylori eradication

Comparison: 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days Outcome: 7 Adverse events: diarrhoea

Study or subgroup

14 days

Dore 2011

10 days

n/N

n/N

3/202

5/215



0.1 0.2

0.5

1

Favours 14 days

2

5

10

Favours 10 days

Analysis 16.8. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 8 Adverse events: glossitis. Review:


pylori eradication

Comparison: 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days Outcome: 8 Adverse events: glossitis

Study or subgroup

Dore 2011

14 days

10 days

n/N

n/N

2/202

0/215



0.001 0.01 0.1 Favours 14 days


1


343

Analysis 16.9. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 9 Adverse events: vaginitis. Review:


pylori eradication

Comparison: 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days Outcome: 9 Adverse events: vaginitis

Study or subgroup

Dore 2011

14 days

10 days

n/N

n/N

1/202

0/215



0.01

0.1

1

Favours 14 days

10

100

Favours 10 days

Analysis 16.10. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 10 Adverse events: dysphagia. Review:


pylori eradication

Comparison: 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days Outcome: 10 Adverse events: dysphagia

Study or subgroup

Dore 2011

14 days

10 days

n/N

n/N

1/202

0/215



0.01

0.1

Favours 14 days


1

10

100

Favours 10 days

344

Analysis 16.11. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 11 Adverse events: dizziness. Review:


pylori eradication

Comparison: 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days Outcome: 11 Adverse events: dizziness

Study or subgroup

Dore 2011

14 days

10 days

n/N

n/N

0/202

1/215



0.01

0.1

1

Favours 14 days

10

100

Favours 10 days

Analysis 16.12. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 12 Adverse events: unfitness/discomfort (patients reported). Review:


pylori eradication

Comparison: 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days Outcome: 12 Adverse events: unfitness/discomfort (patients reported)

Study or subgroup

14 days

10 days

n/N

n/N

Dore 2011

40/202

18/215



0.1 0.2

0.5

Favours 14 days


1

2

5

10

Favours 10 days

345

Analysis 16.13. Comparison 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days, Outcome 13 Adverse events: fatigue/weakness (patients reported). Review:


pylori eradication

Comparison: 16 PPI + bismuth + two antibiotics quadruple therapy, 14 days versus 10 days Outcome: 13 Adverse events: fatigue/weakness (patients reported)

Study or subgroup

Favours 14 days

10 days

n/N

n/N

32/202

20/215

Dore 2011



0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 10 days

Analysis 17.1. Comparison 17 PPI + three antibiotics quadruple therapy, 10 days versus 7 days, Outcome 1 H. pylori persistence. Review:


pylori eradication

Comparison: 17 PPI + three antibiotics quadruple therapy, 10 days versus 7 days Outcome: 1 H.

pylori persistence

Study or subgroup

10 days

7 days

n/N

n/N


Weight


1 Omeprazole+ levofloxacin+ nitazoxanide+ doxycycline Basu 2011

10/90

9/90

100.0 %

1.11 [ 0.47, 2.60 ]

90

90

100.0 %

1.11 [ 0.47, 2.60 ]

Total (95% CI) Total events: 10 (10 days), 9 (7 days) Heterogeneity: not applicable

Test for overall effect: Z = 0.24 (P = 0.81) Test for subgroup differences: Not applicable

0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


346

Analysis 17.2. Comparison 17 PPI + three antibiotics quadruple therapy, 10 days versus 7 days, Outcome 2 Patients discontinuing treatment due to adverse events. Review:


pylori eradication

Comparison: 17 PPI + three antibiotics quadruple therapy, 10 days versus 7 days Outcome: 2 Patients discontinuing treatment due to adverse events

Study or subgroup

10 days

7 days

n/N

n/N


Weight


1 Omeprazole+ levofloxacin+ nitazoxanide+ doxycycline Basu 2011

Total (95% CI)

5/90

3/90

100.0 %

1.67 [ 0.41, 6.77 ]

90

90

100.0 %

1.67 [ 0.41, 6.77 ]


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


347

Analysis 18.1. Comparison 18 PPI dual therapy (PPI + one antibiotic) 14 days versus 7 days, Outcome 1 H. pylori persistence. Review:


pylori eradication

Comparison: 18 PPI dual therapy (PPI + one antibiotic) 14 days versus 7 days Outcome: 1 H.

pylori persistence

Study or subgroup

14 days

7 days

n/N

n/N


Weight


1 High dose PPI (omeprazole 60mg bid)+ Clarithromycin 500mg bid Chew 1994

10/31

9/33

100.0 %

1.18 [ 0.56, 2.52 ]

31

33

100.0 %

1.18 [ 0.56, 2.52 ]



0.1 0.2

0.5

1

Favours 14 days

2

5

10

Favours 7 days

Analysis 18.2. Comparison 18 PPI dual therapy (PPI + one antibiotic) 14 days versus 7 days, Outcome 2 Patients with adverse events. Review:


pylori eradication

Comparison: 18 PPI dual therapy (PPI + one antibiotic) 14 days versus 7 days Outcome: 2 Patients with adverse events

Study or subgroup

Chew 1994

14 days

7 days


Weight


n/N

n/N

10/31

3/33

100.0 %

3.55 [ 1.08, 11.70 ]

31

33

100.0 %

3.55 [ 1.08, 11.70 ]



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


348

Analysis 19.1. Comparison 19 PPI dual therapy (PPI + one antibiotic), 10 days versus 7 days, Outcome 1 H. pylori persistence. Review:


pylori eradication

Comparison: 19 PPI dual therapy (PPI + one antibiotic), 10 days versus 7 days Outcome: 1 H.

pylori persistence

Study or subgroup

10 days

7 days

n/N

n/N


Weight


1 Rabeprazole 20mg od + levofloxacin 500mg od Di Caro 2002a

Total (95% CI)

14/40

12/40

100.0 %

1.17 [ 0.62, 2.20 ]

40

40

100.0 %

1.17 [ 0.62, 2.20 ]


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


349

Analysis 19.2. Comparison 19 PPI dual therapy (PPI + one antibiotic), 10 days versus 7 days, Outcome 2 Patients with adverse events. Review:


pylori eradication

Comparison: 19 PPI dual therapy (PPI + one antibiotic), 10 days versus 7 days Outcome: 2 Patients with adverse events

Study or subgroup

10 days

7 days


Weight


n/N

n/N

Di Caro 2002a

6/40

0/40

100.0 %

13.00 [ 0.76, 223.33 ]

Total (95% CI)

40

40

100.0 %

13.00 [ 0.76, 223.33 ]


0.001 0.01 0.1 Favours 10 days

1


Analysis 19.3. Comparison 19 PPI dual therapy (PPI + one antibiotic), 10 days versus 7 days, Outcome 3 Patients discontinuing treatment due to adverse events. Review:


pylori eradication

Comparison: 19 PPI dual therapy (PPI + one antibiotic), 10 days versus 7 days Outcome: 3 Patients discontinuing treatment due to adverse events

Study or subgroup

10 days

7 days


Weight


n/N

n/N

Di Caro 2002a

0/40

0/40

Not estimable

Total (95% CI)

40

40

Not estimable

Total events: 0 (10 days), 0 (7 days) Heterogeneity: not applicable Test for overall effect: not applicable Test for subgroup differences: Not applicable

0.01

0.1

Favours 10 days

1

10

100

Favours 7 days


350

Analysis 20.1. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 1 H. pylori persistence. Review:


pylori eradication

Comparison: 20 H2 RA bismuth quadruple therapy, 14 days versus 7 days Outcome: 1 H.

pylori persistence

Study or subgroup

14 days

7 days

n/N

n/N


Weight


1 Ranitidine 300mg bid, CBS 240mg bid, amoxicillin 1g bid, metronidazole 500mg bid Kaviani 2001

Total (95% CI)

30/80

61/80

100.0 %

0.49 [ 0.36, 0.67 ]

80

80

100.0 %

0.49 [ 0.36, 0.67 ]

Total events: 30 (14 days), 61 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 4.51 (P < 0.00001) Test for subgroup differences: Not applicable

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


351

Analysis 20.2. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 2 Patients discontinuing treatment due to adverse events. Review:


pylori eradication

Comparison: 20 H2 RA bismuth quadruple therapy, 14 days versus 7 days Outcome: 2 Patients discontinuing treatment due to adverse events

Study or subgroup

14 days

7 days

n/N

n/N

1/80

0/80

100.0 %

3.00 [ 0.12, 72.56 ]

80

80

100.0 %

3.00 [ 0.12, 72.56 ]

Kaviani 2001

Total (95% CI)


Weight



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days

Analysis 20.3. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 3 Adverse event: Anorexia. Review:


pylori eradication

Comparison: 20 H2 RA bismuth quadruple therapy, 14 days versus 7 days Outcome: 3 Adverse event: Anorexia

Study or subgroup

Kaviani 2001

14 days

7 days

n/N

n/N

9/68

10/64



0.1 0.2

0.5

Favours 14 days


1

2

5

10

Favours 7 days

352

Analysis 20.4. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 4 Adverse event: Nausea. Review:


pylori eradication

Comparison: 20 H2 RA bismuth quadruple therapy, 14 days versus 7 days Outcome: 4 Adverse event: Nausea

Study or subgroup

14 days

Kaviani 2001

7 days

n/N

n/N

10/68

6/64



0.1 0.2

0.5

1

Favours 14 days

2

5

10

Favours 7 days

Analysis 20.5. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 5 Adverse event: Vomiting. Review:


pylori eradication

Comparison: 20 H2 RA bismuth quadruple therapy, 14 days versus 7 days Outcome: 5 Adverse event: Vomiting

Study or subgroup

Kaviani 2001

14 days

7 days

n/N

n/N

1/68

1/64



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

353

Analysis 20.6. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 6 Adverse event: Diarrhoea. Review:


pylori eradication

Comparison: 20 H2 RA bismuth quadruple therapy, 14 days versus 7 days Outcome: 6 Adverse event: Diarrhoea

Study or subgroup

Kaviani 2001

14 days

7 days

n/N

n/N

5/68

6/64



0.1 0.2

0.5

1

Favours 14 days

2

5

10

Favours 7 days

Analysis 20.7. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 7 Adverse event: Constipation. Review:


pylori eradication

Comparison: 20 H2 RA bismuth quadruple therapy, 14 days versus 7 days Outcome: 7 Adverse event: Constipation

Study or subgroup

Kaviani 2001

14 days

7 days

n/N

n/N

2/68

5/64



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

354

Analysis 20.8. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 8 Adverse event; Dizziness. Review:


pylori eradication

Comparison: 20 H2 RA bismuth quadruple therapy, 14 days versus 7 days Outcome: 8 Adverse event; Dizziness

Study or subgroup

14 days

Kaviani 2001

7 days

n/N

n/N

9/68

12/64



0.1 0.2

0.5

1

Favours 14 days

2

5

10

Favours 7 days

Analysis 20.9. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 9 Adverse event: Headache. Review:


pylori eradication

Comparison: 20 H2 RA bismuth quadruple therapy, 14 days versus 7 days Outcome: 9 Adverse event: Headache

Study or subgroup

Kaviani 2001

14 days

7 days

n/N

n/N

9/68

8/64



0.1 0.2

0.5

Favours 14 days


1

2

5

10

Favours 7 days

355

Analysis 20.10. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 10 Adverse event: Fatigue. Review:


pylori eradication

Comparison: 20 H2 RA bismuth quadruple therapy, 14 days versus 7 days Outcome: 10 Adverse event: Fatigue

Study or subgroup

Kaviani 2001

14 days

7 days

n/N

n/N

13/68

20/64



0.1 0.2

0.5

1

Favours 14 days

2

5

10

Favours 7 days

Analysis 20.11. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 11 Adverse event: Unpleasant taste. Review:


pylori eradication

Comparison: 20 H2 RA bismuth quadruple therapy, 14 days versus 7 days Outcome: 11 Adverse event: Unpleasant taste

Study or subgroup

Kaviani 2001

14 days

7 days

n/N

n/N

35/68

27/64



0.1 0.2

0.5

Favours 14 days


1

2

5

10

Favours 7 days

356

Analysis 20.12. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 12 Adverse event: Dry mouth. Review:


pylori eradication

Comparison: 20 H2 RA bismuth quadruple therapy, 14 days versus 7 days Outcome: 12 Adverse event: Dry mouth

Study or subgroup

Kaviani 2001

14 days

7 days

n/N

n/N

28/68

25/64



0.1 0.2

0.5

1

Favours 14 days

2

5

10

Favours 7 days

Analysis 20.13. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 13 Adverse event: Anal itching. Review:


pylori eradication

Comparison: 20 H2 RA bismuth quadruple therapy, 14 days versus 7 days Outcome: 13 Adverse event: Anal itching

Study or subgroup

Kaviani 2001

14 days

7 days

n/N

n/N

2/68

0/64



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

357

Analysis 20.14. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 14 Adverse event: Dysuria. Review:


pylori eradication

Comparison: 20 H2 RA bismuth quadruple therapy, 14 days versus 7 days Outcome: 14 Adverse event: Dysuria

Study or subgroup

14 days

7 days

n/N

n/N

4/68

6/64

Kaviani 2001



0.1 0.2

0.5

1

Favours 14 days

2

5

10

Favours 7 days

Analysis 20.15. Comparison 20 H2RA bismuth quadruple therapy, 14 days versus 7 days, Outcome 15 Adverse event: Urticaria. Review:


pylori eradication

Comparison: 20 H2 RA bismuth quadruple therapy, 14 days versus 7 days Outcome: 15 Adverse event: Urticaria

Study or subgroup

Kaviani 2001

14 days

7 days

n/N

n/N

1/68

3/64



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

358

Analysis 21.1. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 1 H. pylori persistence, subgroup by regimen. Review:


pylori eradication

Comparison: 21 H2 RA bismuth quadruple therapy, 10 days versus 7 days Outcome: 1 H.


Study or subgroup

10 days

7 days

n/N

n/N


Weight


1 RBC 400mg bid + metronidazole 500mg bid+ tetracycline 500mg bid Knigge 1999

Subtotal (95% CI)

20/51

24/54

78.9 %

0.88 [ 0.56, 1.39 ]

51

54

78.9 %

0.88 [ 0.56, 1.39 ]

Total events: 20 (10 days), 24 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 0.54 (P = 0.59) 2 RBC 400mg bid+ metronidazole 500mg bid+ clarithromycin 250mg bid Savarino 1999

Subtotal (95% CI)

8/55

9/55

21.1 %

0.89 [ 0.37, 2.13 ]

55

55

21.1 %

0.89 [ 0.37, 2.13 ]

109

100.0 %

0.88 [ 0.59, 1.32 ]


Total (95% CI)

106


0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days


359

Analysis 21.2. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 2 Patients with adverse event. Review:


pylori eradication

Comparison: 21 H2 RA bismuth quadruple therapy, 10 days versus 7 days Outcome: 2 Patients with adverse event

Study or subgroup

10 days

7 days


Weight


n/N

n/N

Knigge 1999

29/51

30/54

85.8 %

1.02 [ 0.73, 1.43 ]

Savarino 1999

11/55

8/55

14.2 %

1.38 [ 0.60, 3.15 ]

Total (95% CI)

106

109

100.0 %

1.07 [ 0.78, 1.46 ]


0.1 0.2

0.5

1

Favours 10 days

2

5

10

Favours 7 days

Analysis 21.3. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 3 Patients discontinuing treatment due to adverse events. Review:


pylori eradication

Comparison: 21 H2 RA bismuth quadruple therapy, 10 days versus 7 days Outcome: 3 Patients discontinuing treatment due to adverse events

Study or subgroup

10 days

7 days


Weight


n/N

n/N

Savarino 1999

3/55

1/55

100.0 %

3.00 [ 0.32, 27.96 ]

Total (95% CI)

55

55

100.0 %

3.00 [ 0.32, 27.96 ]


0.01

0.1

Favours 10 days

1

10

100

Favours 7 days


360

Analysis 21.4. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 4 Adverse event: Epigastric pain. Review:


pylori eradication

Comparison: 21 H2 RA bismuth quadruple therapy, 10 days versus 7 days Outcome: 4 Adverse event: Epigastric pain

Study or subgroup

Savarino 1999

10 days

7 days

n/N

n/N

5/55

3/55



0.1 0.2

0.5

1

Favours 10 days

2

5

10

Favours 7 days

Analysis 21.5. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 5 Adverse event: Nausea. Review:


pylori eradication

Comparison: 21 H2 RA bismuth quadruple therapy, 10 days versus 7 days Outcome: 5 Adverse event: Nausea

Study or subgroup

Savarino 1999

10 days

7 days

n/N

n/N

4/55

4/55



0.1 0.2

0.5

Favours 10 days


1

2

5

10

Favours 7 days

361

Analysis 21.6. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 6 Adverse event: Diarrhoea. Review:


pylori eradication

Comparison: 21 H2 RA bismuth quadruple therapy, 10 days versus 7 days Outcome: 6 Adverse event: Diarrhoea

Study or subgroup

10 days

Savarino 1999

7 days

n/N

n/N

3/55

2/55



0.1 0.2

0.5

1

Favours 10 days

2

5

10

Favours 7 days

Analysis 21.7. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 7 Adverse event: Vomiting. Review:


pylori eradication

Comparison: 21 H2 RA bismuth quadruple therapy, 10 days versus 7 days Outcome: 7 Adverse event: Vomiting

Study or subgroup

Savarino 1999

10 days

7 days

n/N

n/N

3/55

1/55



0.01

0.1

Favours 10 days


1

10

100

Favours 7 days

362

Analysis 21.8. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 8 Adverse event: Headache. Review:


pylori eradication

Comparison: 21 H2 RA bismuth quadruple therapy, 10 days versus 7 days Outcome: 8 Adverse event: Headache

Study or subgroup

10 days

Savarino 1999

7 days

n/N

n/N

2/55

2/55



0.1 0.2

0.5

1

Favours 10 days

2

5

10

Favours 7 days

Analysis 21.9. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 9 Adverse event: Skin rash. Review:


pylori eradication

Comparison: 21 H2 RA bismuth quadruple therapy, 10 days versus 7 days Outcome: 9 Adverse event: Skin rash

Study or subgroup

Savarino 1999

10 days

7 days

n/N

n/N

1/55

1/55



0.01

0.1

Favours 10 days


1

10

100

Favours 7 days

363

Analysis 21.10. Comparison 21 H2RA bismuth quadruple therapy, 10 days versus 7 days, Outcome 10 Adverse event: Taste disturbance. Review:


pylori eradication

Comparison: 21 H2 RA bismuth quadruple therapy, 10 days versus 7 days Outcome: 10 Adverse event: Taste disturbance

Study or subgroup

10 days

Savarino 1999

7 days

n/N

n/N

5/55

4/55



0.1 0.2

0.5

Favours 10 days

1

2

5

10

Favours 7 days

Analysis 22.1. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 1 H. pylori persistence. Review:


pylori eradication

Comparison: 22 H2 RA bismuth-based triple therapy, 14 days versus 7 days Outcome: 1 H.

pylori persistence

Study or subgroup

14 days

7 days

n/N

n/N


Weight


1 RBC 400mg bid and clarithromycin 500mg bid Pozzato 1998

11/56

14/56

43.3 %

0.79 [ 0.39, 1.58 ]

Mesquita 2005

14/58

17/62

56.7 %

0.88 [ 0.48, 1.62 ]

Total (95% CI)

114

118

100.0 %

0.84 [ 0.53, 1.33 ]


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


364

Analysis 22.2. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 2 Patients with adverse events. Review:


pylori eradication

Comparison: 22 H2 RA bismuth-based triple therapy, 14 days versus 7 days Outcome: 2 Patients with adverse events

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Pozzato 1998

1/56

3/56

24.2 %

0.33 [ 0.04, 3.11 ]

Mesquita 2005

4/53

5/56

75.8 %

0.85 [ 0.24, 2.98 ]

Total (95% CI)

109

112

100.0 %

0.68 [ 0.23, 2.02 ]


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


365

Analysis 22.3. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 3 Patients discontinuing treatment due to adverse events. Review:


pylori eradication

Comparison: 22 H2 RA bismuth-based triple therapy, 14 days versus 7 days Outcome: 3 Patients discontinuing treatment due to adverse events

Study or subgroup

14 days

7 days

n/N

n/N

Pozzato 1998

0/56

1/56

Mesquita 2005

0/53

0/56

Total (95% CI)

109

112


Weight

100.0 %


100.0 %

0.33 [ 0.01, 8.01 ]


0.01

0.1

Favours 14 days

1

10

100

Favours 7 days

Analysis 22.4. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 4 Adverse event: Nausea. Review:


pylori eradication

Comparison: 22 H2 RA bismuth-based triple therapy, 14 days versus 7 days Outcome: 4 Adverse event: Nausea

Study or subgroup

Pozzato 1998

14 days

7 days

n/N

n/N

0/56

1/56



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

366

Analysis 22.5. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 5 Adverse event: Headache. Review:


pylori eradication

Comparison: 22 H2 RA bismuth-based triple therapy, 14 days versus 7 days Outcome: 5 Adverse event: Headache

Study or subgroup

Pozzato 1998

14 days

7 days

n/N

n/N

0/56

1/56



0.01

0.1

1

Favours 14 days

10

100

Favours 7 days

Analysis 22.6. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 6 Adverse event: Pruritus. Review:


pylori eradication

Comparison: 22 H2 RA bismuth-based triple therapy, 14 days versus 7 days Outcome: 6 Adverse event: Pruritus

Study or subgroup

Pozzato 1998

14 days

7 days

n/N

n/N

1/56

0/56



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

367

Analysis 22.7. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 7 Adverse event: Allergic dermatitis. Review:


pylori eradication

Comparison: 22 H2 RA bismuth-based triple therapy, 14 days versus 7 days Outcome: 7 Adverse event: Allergic dermatitis

Study or subgroup

Pozzato 1998

14 days

7 days

n/N

n/N

0/56

1/56



0.01

0.1

1

Favours 14 days

10

100

Favours 7 days

Analysis 22.8. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 8 Adverse event: Conjunctivitis. Review:


pylori eradication

Comparison: 22 H2 RA bismuth-based triple therapy, 14 days versus 7 days Outcome: 8 Adverse event: Conjunctivitis

Study or subgroup

Pozzato 1998

14 days

7 days

n/N

n/N

0/56

1/56



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

368

Analysis 22.9. Comparison 22 H2RA bismuth-based triple therapy, 14 days versus 7 days, Outcome 9 Adverse event: Asthenia. Review:


pylori eradication

Comparison: 22 H2 RA bismuth-based triple therapy, 14 days versus 7 days Outcome: 9 Adverse event: Asthenia

Study or subgroup

14 days

Pozzato 1998

7 days

n/N

n/N

0/56

1/56



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days

Analysis 23.1. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 1 H. pylori persistence, subgroup by regimen. Review:


pylori eradication

Comparison: 23 H2 RA triple therapy (H2 RA + two antibiotics), 14 days versus 7 days Outcome: 1 H.


Study or subgroup

14 days

7 days

n/N

n/N


Weight


1 Famotidine 20mg bid, amoxicillin 1g bid, metronidazole 400mg bid Hu 2003

Subtotal (95% CI)

7/38

11/25

23.7 %

0.42 [ 0.19, 0.93 ]

38

25

23.7 %

0.42 [ 0.19, 0.93 ]

Total events: 7 (14 days), 11 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 2.13 (P = 0.033) 2 Famotidine 40mg bid, amoxicillin 1g bid, tinidazole 500mg bid Hsu 2005

Subtotal (95% CI)

12/60

22/60

33.6 %

0.55 [ 0.30, 1.00 ]

60

60

33.6 %

0.55 [ 0.30, 1.00 ]

Total events: 12 (14 days), 22 (7 days) Heterogeneity: not applicable

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days

(Continued . . . )


369


14 days

7 days

n/N

n/N


Weight


Test for overall effect: Z = 1.96 (P = 0.050) 3 Lufatidine 20mg bid, clarithromycin 500mg bid, amoxicillin 1g bid Kim 2008

26/119

27/115

42.7 %

0.93 [ 0.58, 1.49 ]

119

115

42.7 %

0.93 [ 0.58, 1.49 ]

200

100.0 %

0.64 [ 0.40, 1.03 ]



Total (95% CI)

217


0.1 0.2

0.5

1

Favours 14 days

2

5

10

Favours 7 days

Analysis 23.2. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 2 H. pylori persistence, subgroup by location. Review:


pylori eradication



Study or subgroup

14 days

7 days


Weight


n/N

n/N

Hu 2003

7/38

11/25

23.7 %

0.42 [ 0.19, 0.93 ]

Hsu 2005

12/60

22/60

33.6 %

0.55 [ 0.30, 1.00 ]

Kim 2008

26/119

27/115

42.7 %

0.93 [ 0.58, 1.49 ]

217

200

100.0 %

0.64 [ 0.40, 1.03 ]

1 Asian countries

Total (95% CI)


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


370

Analysis 23.3. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 3 H. pylori persistence, subgroup by baseline PUD or FD. Review:


pylori eradication



Study or subgroup

14 days

7 days


Weight


n/N

n/N

26/119

27/115

42.7 %

0.93 [ 0.58, 1.49 ]

119

115

42.7 %

0.93 [ 0.58, 1.49 ]

1 PUD patients Kim 2008


Test for overall effect: Z = 0.30 (P = 0.77) 2 Mixed PUD and FD or gastritis patients Hu 2003

7/38

11/25

23.7 %

0.42 [ 0.19, 0.93 ]

Hsu 2005

12/60

22/60

33.6 %

0.55 [ 0.30, 1.00 ]

98

85

57.3 %

0.50 [ 0.31, 0.80 ]

100.0 %

0.64 [ 0.40, 1.03 ]



Total (95% CI)

217

200


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


371

Analysis 23.4. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 4 H. pylori persistence, subgroup by risk of bias: allocation concealment. Review:


pylori eradication



Study or subgroup

14 days

7 days


Weight


n/N

n/N

26/119

27/115

42.7 %

0.93 [ 0.58, 1.49 ]

119

115

42.7 %

0.93 [ 0.58, 1.49 ]

1 low risk of bias Kim 2008


Test for overall effect: Z = 0.30 (P = 0.77) 2 Unclear risk of bias Hu 2003

7/38

11/25

23.7 %

0.42 [ 0.19, 0.93 ]

Hsu 2005

12/60

22/60

33.6 %

0.55 [ 0.30, 1.00 ]

98

85

57.3 %

0.50 [ 0.31, 0.80 ]

100.0 %

0.64 [ 0.40, 1.03 ]



Total (95% CI)

217

200


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


372

Analysis 23.5. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 5 H. pylori persistence, subgroup by risk of bias: overall. Review:


pylori eradication



Study or subgroup

14 days

7 days


Weight


n/N

n/N

26/119

27/115

42.7 %

0.93 [ 0.58, 1.49 ]

119

115

42.7 %

0.93 [ 0.58, 1.49 ]

1 low risk of bias Kim 2008


Test for overall effect: Z = 0.30 (P = 0.77) 2 High risk of bias Hu 2003

7/38

11/25

23.7 %

0.42 [ 0.19, 0.93 ]

Hsu 2005

12/60

22/60

33.6 %

0.55 [ 0.30, 1.00 ]

98

85

57.3 %

0.50 [ 0.31, 0.80 ]

100.0 %

0.64 [ 0.40, 1.03 ]



Total (95% CI)

217

200


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


373

Analysis 23.6. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 6 Patients with adverse events. Review:


pylori eradication

Comparison: 23 H2 RA triple therapy (H2 RA + two antibiotics), 14 days versus 7 days Outcome: 6 Patients with adverse events

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Hsu 2005

6/60

7/60

34.1 %

0.86 [ 0.31, 2.40 ]

Kim 2008

17/119

10/115

65.9 %

1.64 [ 0.79, 3.44 ]

179

175

100.0 %

1.32 [ 0.72, 2.41 ]

Total (95% CI)


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


374

Analysis 23.7. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 7 Patients discontinuing treatment due to adverse events. Review:


pylori eradication

Comparison: 23 H2 RA triple therapy (H2 RA + two antibiotics), 14 days versus 7 days Outcome: 7 Patients discontinuing treatment due to adverse events

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Hu 2003

0/38

0/25

Not estimable

Hsu 2005

0/60

0/60

Not estimable

Kim 2008

0/119

1/115

100.0 %

0.32 [ 0.01, 7.83 ]

217

200

100.0 %

0.32 [ 0.01, 7.83 ]



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


375

Analysis 23.8. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 8 Adverse event: Diarrhoea. Review:


pylori eradication

Comparison: 23 H2 RA triple therapy (H2 RA + two antibiotics), 14 days versus 7 days Outcome: 8 Adverse event: Diarrhoea

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Hsu 2005

4/60

4/60

32.1 %

1.00 [ 0.26, 3.81 ]

Kim 2008

14/119

6/115

67.9 %

2.25 [ 0.90, 5.67 ]

179

175

100.0 %

1.74 [ 0.81, 3.71 ]

Total (95% CI)


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


376

Analysis 23.9. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 9 Adverse event: Nausea or Vomiting. Review:


pylori eradication

Comparison: 23 H2 RA triple therapy (H2 RA + two antibiotics), 14 days versus 7 days Outcome: 9 Adverse event: Nausea or Vomiting

Study or subgroup

14 days

7 days

n/N

n/N

Hsu 2005

1/60

1/60

17.2 %

1.00 [ 0.06, 15.62 ]

Kim 2008

11/119

3/115

82.8 %

3.54 [ 1.01, 12.38 ]

179

175

100.0 %

2.85 [ 0.91, 8.90 ]

Total (95% CI)


Weight



0.01

0.1

1

Favours 14 days

10

100

Favours 7 days

Analysis 23.10. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 10 Adverse event: Headache. Review:


pylori eradication

Comparison: 23 H2 RA triple therapy (H2 RA + two antibiotics), 14 days versus 7 days Outcome: 10 Adverse event: Headache

Study or subgroup

Hsu 2005

14 days

7 days

n/N

n/N

0/60

1/60



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

377

Analysis 23.11. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 11 Adverse event: Taste alteration. Review:


pylori eradication

Comparison: 23 H2 RA triple therapy (H2 RA + two antibiotics), 14 days versus 7 days Outcome: 11 Adverse event: Taste alteration

Study or subgroup

Hsu 2005

14 days

7 days

n/N

n/N

1/60

1/60



0.01

0.1

1

Favours 14 days

10

100

Favours 7 days

Analysis 23.12. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 12 Adverse event: Epigastric discomfort. Review:


pylori eradication

Comparison: 23 H2 RA triple therapy (H2 RA + two antibiotics), 14 days versus 7 days Outcome: 12 Adverse event: Epigastric discomfort

Study or subgroup

Kim 2008

14 days

7 days

n/N

n/N

1/119

1/115



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

378

Analysis 23.13. Comparison 23 H2RA triple therapy (H2RA + two antibiotics), 14 days versus 7 days, Outcome 13 Adverse event: Dizziness. Review:


pylori eradication

Comparison: 23 H2 RA triple therapy (H2 RA + two antibiotics), 14 days versus 7 days Outcome: 13 Adverse event: Dizziness

Study or subgroup

14 days

Kim 2008

7 days

n/N

n/N

1/119

0/115



0.01

0.1

Favours 14 days

1

10

100

Favours 7 days

Analysis 24.1. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 1 H. pylori persistence, subgroup by regimen. Review:


pylori eradication

Comparison: 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days Outcome: 1 H.


Study or subgroup

14 days

7 days

n/N

n/N


Weight


1 Bismuth Subsalicylate 250mg bid, tetracycline 500mg bid, metronidazole 250mg bid Muszynki 1992

Subtotal (95% CI)

6/21

9/21

71.8 %

0.67 [ 0.29, 1.54 ]

21

21

71.8 %

0.67 [ 0.29, 1.54 ]

Total events: 6 (14 days), 9 (7 days) Heterogeneity: not applicable Test for overall effect: Z = 0.95 (P = 0.34) 2 CBS 120mg qid, tetracycline 500mg qid, metronidazole 500mg bid de Boer 1994

Subtotal (95% CI)

4/54

4/57

28.2 %

1.06 [ 0.28, 4.01 ]

54

57

28.2 %

1.06 [ 0.28, 4.01 ]

Total events: 4 (14 days), 4 (7 days) Heterogeneity: not applicable

0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days

(Continued . . . )


379


14 days

7 days

n/N

n/N


Weight



Total (95% CI)

75

100.0 %

78

0.76 [ 0.37, 1.54 ]


0.1 0.2

0.5

1

Favours 14 days

2

5

10

Favours 7 days

Analysis 24.2. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 2 Patients with adverse events. Review:


pylori eradication

Comparison: 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days Outcome: 2 Patients with adverse events

Study or subgroup

14 days

7 days


Weight


n/N

n/N

de Boer 1994

46/53

45/56

93.2 %

1.08 [ 0.91, 1.28 ]

Muszynki 1992

12/21

9/21

6.8 %

1.33 [ 0.72, 2.47 ]

74

77

100.0 %

1.10 [ 0.93, 1.29 ]

Total (95% CI)


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


380

Analysis 24.3. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 3 Patients discontinuing treatment due to adverse events. Review:


pylori eradication

Comparison: 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days Outcome: 3 Patients discontinuing treatment due to adverse events

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Muszynki 1992

4/21

2/21

77.0 %

2.00 [ 0.41, 9.77 ]

de Boer 1994

4/53

0/56

23.0 %

9.50 [ 0.52, 172.30 ]

Total (95% CI)

74

77

100.0 %

2.86 [ 0.71, 11.51 ]


0.001 0.01 0.1 Favours 14 days

1



381

Analysis 24.4. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 4 Adverse event: Nausea. Review:


pylori eradication

Comparison: 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days Outcome: 4 Adverse event: Nausea

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Muszynki 1992

9/21

8/21

27.4 %

1.13 [ 0.54, 2.35 ]

de Boer 1994

25/53

20/56

72.6 %

1.32 [ 0.84, 2.08 ]

74

77

100.0 %

1.26 [ 0.86, 1.86 ]

Total (95% CI)


0.1 0.2

0.5

Favours 14 days

1

2

5

10

Favours 7 days


382

Analysis 24.5. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 5 Adverse event: Vomiting. Review:


pylori eradication

Comparison: 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days Outcome: 5 Adverse event: Vomiting

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Muszynki 1992

2/21

0/21

13.4 %

5.00 [ 0.25, 98.27 ]

de Boer 1994

7/53

4/56

86.6 %

1.85 [ 0.57, 5.96 ]

Total (95% CI)

74

77

100.0 %

2.11 [ 0.71, 6.27 ]


0.01

0.1

Favours 14 days

1

10

100

Favours 7 days


383

Analysis 24.6. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 6 Adverse event: Metalic taste or bad taste. Review:


pylori eradication

Comparison: 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days Outcome: 6 Adverse event: Metalic taste or bad taste

Study or subgroup

14 days

7 days


Weight


n/N

n/N

Muszynki 1992

1/21

0/21

1.2 %

3.00 [ 0.13, 69.70 ]

de Boer 1994

29/53

31/56

98.8 %

0.99 [ 0.70, 1.39 ]

74

77

100.0 %

1.00 [ 0.71, 1.40 ]

Total (95% CI)


0.01

0.1

Favours 14 days

1

10

100

Favours 7 days

Analysis 24.7. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 7 Adverse event: Heartburn. Review:


pylori eradication

Comparison: 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days Outcome: 7 Adverse event: Heartburn

Study or subgroup

14 days

7 days

n/N

n/N

Muszynki 1992

2/21

0/21



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

384

Analysis 24.8. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 8 Adverse event: Diarrhoea. Review:


pylori eradication

Comparison: 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days Outcome: 8 Adverse event: Diarrhoea

Study or subgroup

de Boer 1994

14 days

7 days

n/N

n/N

23/53

27/56



0.1 0.2

0.5

1

Favours 14 days

2

5

10

Favours 7 days

Analysis 24.9. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 9 Adverse event: Stomach pain. Review:


pylori eradication

Comparison: 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days Outcome: 9 Adverse event: Stomach pain

Study or subgroup

de Boer 1994

14 days

7 days

n/N

n/N

2/53

12/56



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

385

Analysis 24.10. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 10 Adverse event: Burning sensation in the oesophagus. Review:


pylori eradication

Comparison: 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days Outcome: 10 Adverse event: Burning sensation in the oesophagus

Study or subgroup

Muszynki 1992

14 days

7 days

n/N

n/N

1/21

0/21



0.01

0.1

1

Favours 14 days

10

100

Favours 7 days

Analysis 24.11. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 11 Adverse event: Burning sensation in the mouth. Review:


pylori eradication

Comparison: 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days Outcome: 11 Adverse event: Burning sensation in the mouth

Study or subgroup

14 days

7 days

n/N

n/N

Muszynki 1992

1/21

0/21



0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

386

Analysis 24.12. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 12 Adverse event: Dysphagia. Review:


pylori eradication

Comparison: 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days Outcome: 12 Adverse event: Dysphagia

Study or subgroup

14 days

7 days

n/N

n/N

1/21

0/21

Muszynki 1992



0.01

0.1

1

Favours 14 days

10

100

Favours 7 days

Analysis 24.13. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 13 Adverse event: Burping. Review:


pylori eradication

Comparison: 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days Outcome: 13 Adverse event: Burping

Study or subgroup

14 days

7 days

n/N

n/N

Muszynki 1992

0/21

1/21


Odds Ratio MH,Random,95% CI 0.32 [ 0.01, 8.26 ]

0.01

0.1

Favours 14 days


1

10

100

Favours 7 days

387

Analysis 24.14. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 14 Adverse event: Anorexia. Review:


pylori eradication

Comparison: 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days Outcome: 14 Adverse event: Anorexia

Study or subgroup

de Boer 1994

14 days

7 days

n/N

n/N

15/53

10/56



0.1 0.2

0.5

1

Favours 14 days

2

5

10

Favours 7 days

Analysis 24.15. Comparison 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days, Outcome 15 Adverse event: Dizziness. Review:


pylori eradication

Comparison: 24 Bismuth triple therapy (bismuth salt + two antibiotics), 14 days versus 7 days Outcome: 15 Adverse event: Dizziness

Study or subgroup

de Boer 1994

14 days

7 days

n/N

n/N

10/53

11/56



0.1 0.2

0.5

Favours 14 days


1

2

5

10

Favours 7 days

388

ADDITIONAL TABLES Table 1. Pooled effect estimated for different durations Studies (n=75)

14 vs 7 days

10 vs 7 days

14 vs 10 days

RR for H. pylori persistent (95% CI); NNT (95% CI); studies (n) PPI triple therapy (n=59)

RR 0.66 ( 0.60 to 0.74); NNT 11 (9 to 14); (n=45)

RR 0.80 (0.72 to 0.89); NNT 21 (15 to 38); (n=24)

RR 0.72 (0.58 to 0.90); NNT 17 (11 to 46); (n=12)

PCA

RR 0.65 (0.57 to 0.75): NNT 12 (9 to 16); (n=34)

RR 0.80 (0.70 to 0.91); NNT 21 (14 to 48); (n=17)

RR 0.69 (0.52 to 0.91); NNT 16 (10 to 54); (n=10)

PCN

RR 0.87 (0.71 to 1.07); (n=4)

RR 0.99 (0.55 to 1.79); (n=2)

-

PAN

RR 0.67 (0.52 to 0.86); NNT 11 (8 to 25); (n=10)

RR 0.85 (0.65 to 1.12); (n=4)

RR 0.79 (0.54 to 1.15); (n=4)

PAQ

RR 0.37 (0.16 to 0.83); NNT 3 (2 to 10); (n=2)

RR 0.58 (0.36 to 0.95); NNT 7(5 to 59); (n=2)

-

PANi

-

RR 0.79 (0.52 to 1.20); (n=1)

-

PPI bismuth quadruple therapy RR 0.71 (0.44 to 1.15); (n=6) (n=3)

RR 0.70 (0.43 to 1.14); (n=2)

RR 1.13 (0.59 to 2.18); (n=1)

PPI + thee antibiotics quadruple therapy (n=1)

RR 1.11 (0.47 to 2.60): (n=1)

PPI dual therapy (n=2)

RR 1.18 (0.56 to 2.52); (n=1)

RR 1.17 (0.62 to 2.20); (n=1)

-

H2 RA bismuth quadruple ther- RR 0.49 (0.36 to 0.67); apy (n=3) NNT 3 (2 to 4); (n=1)

RR 0.88 (0.59 to 1.32); (n=2)

-

H2 RA bismuth triple therapy RR 0.84 (0.53 to 1.33); (n=2) (n=2)

-

-

H2 RA + two antibiotics triple RR0.64 (0.40 to 1.03); therapy (n=3) (n=3)

-

-

Bismuth (Bismuth salt + two RR 0.76 (0.37 to 1.54); antibiotics) triple therapy (n=2) (n=2)

-

-


389

PCA, a triple regimen contains a proton pump inhibitor, clarithromycin, and amoxicillin; PAN, a triple regimen contains a proton pump inhibitor, clarithromycin and a nitromidazole; PAQ: a triple regimen contains a proton pump inhibitor, amoxicillin and a quinolone. PANi, a triple regimen contains a proton pump inhibitor, amoxicillin and a nitrofuran. N, nitroimidazole: metronidazole or tinidazole was used.

Table 2. Characters of published meta-analyses that compared different durations of H. pylori eradication regimens, and the comparisons with current meta-analysis

Calvet 2000

Ford 2003

Fuccio 2007

Kim 2001

Jung 2008

Flores 2010

Current analysis

meta-

DDW abstract

DDW abstract

DDW abstract

Cochrane review

MEDLINE, EMBASE, The CENTRAL, CINAHL, ProQuest dissertations and theses database; Grey literature databases, up to Dec 2011. Personal databases, filed experts and pharmaceutical companies were searched for relevant trials

Publi- Jourcation nal arformat ticle (journal article or abstract)

Journal article Journal article (duration part was part of a meta-analysis)

MedSearched line 1990 literature to databases 1999 and years

Updated from PubMed, Trials published in Korea the Calvet 2000 EMBASE, no detailed info meta. No details the Cochrane Library through May 2007

Trials published in Korea; Jan. 1996 to Sep. 2007

Pubmed, The Cochrane Library, the Health Research and Development Network, and EMBASE through January 2009

AGA Searched 1995 confer- to ence 1998; proEHceedPSG ings 1996 to 1998

No details

No

UEGW, DDW, DDW, ACG, 1995 to 2007 UEGW, BSG, EHPSG, WCOG, ProceedingsFirst database, up to Dec 2011

Language

No language re- English only striction

Trials published

No language re- No language restriction striction

No language

UEGW and EH- No PSG 1995 to 2006; DDW through 2007

Trials published in Korea


390

Table 2. Characters of published meta-analyses that compared different durations of H. pylori eradication regimens, and the comparisons with current meta-analysis (Continued) restriction

in Korea

Criteria for H. pylori eradication regimens

A PPI PPI triple ther+ clar- apy 7days vs 10 ithromycin days, 7 days vs 14 and days. No specific amoxy- details as a part of cillin a meta-analysis or a nitroimidazole, all twice daily, for between 7 and 14 days

RCTs with RCTs of OAC (7 vs 10 vs OAC at least 2 par- 14 days) (7 allel groups that vs 10 vs compared differ14 ent durations (7 days) vs 10 days or 7 vs 14 days) of identical PPIbased triple therapy PCA or PCM, all given twice daily and at recommend doses, first line therapy

(10 or 14 days) of PPI triple therapy vs 7days treatment duration in terms of H. pylori eradication

RCTs with at least 2 parallel groups that compared different durations (7, 10 or 14 days) of identical H. pylori eradication regimen, regardless the type and dose of the individual medication. First-line therapy

Criteria for H. pylori diagnosis before treatment

By two NA different diagnostic tests

By at NA least 1 high-accuracy diagnostic test (UBT, stool antigen test, gastric mucosal biopsy for histology, RUT or culture)

NA

NA

At least one positive test for H. pylori on the basis of RUT, histology, culture, or UBT or a HpSA test

Crite- Histol- NA ria for ogy or H. py- UBT lori eradication after treatment

“Based on an ap- NA propriate diagnostic test” which quoted the Maastricht III consensus report

NA

NA

By RUT, histology, culture, UBT or a HpSA at least 28 days after completion of eradication treatment

H. pylori eradica- H. pylori eradication tion (Number of patients in whom H. pylori infection was successfully eradicated) ITT

H. py- H. pylori eradicalori tion and adverse eradi- event cation

Outcomes

Eradi- H. pylori positive caafter eradication tion of H. pylori infection and side-


H. pylori persistence after eradication, and, adverse events after eradication therapy. Results used desirable out-

391

Table 2. Characters of published meta-analyses that compared different durations of H. pylori eradication regimens, and the comparisons with current meta-analysis (Continued) come (H. pylori eradicated) were also reported when the RR very closed to 1 as planned a priori

effect of therapy

Required report of ITT results

No. NA Articles that did not specify the type of analysis were assumed to report per protocol data

Yes (n= NA Whether 4) included studies only reported results based on PP sample and did not allow for estimation of ITT results

Only included NA studies report of ITT results. The authors took authors’ ITT data as their ITT data in the analysis

NA

NA

Only included studies reported of ITT results. Any randomized subjects will be included into the ITT analysis. Included all studies that authors reported as ITT analysis, but data from studies with more relaxed ITT definitions were analyzed again in the sensitivity analysis

No

NA

NA

No

NA


392

Table 2. Characters of published meta-analyses that compared different durations of H. pylori eradication regimens, and the comparisons with current meta-analysis (Continued) AnalPeto Risk ratio, fixedysis odds effect model method ratio, assumptionfree model or fixedeffect model

Relative risk, Odds ratio used both fixedeffect model and a random- effects model. Because of the identical results, only present fixed-effect model results

Odds ratio

RR

Relative risk, random- effects model. Fixed-effect model was used in sensitivity analysis. Odds ratio was reported when RR very closed to 1 as planned a priori.

Risk of No bias assessment

No

Jadad scale 3 NA items, total score 1 to 5

NA

NA

Risk of bias table with eight risk domains. No quality scores are given

Publi- No cation bias assessment

No

Yes, funnel plots NA of RR versus the reciprocal of the SE, Begg and Egger tests

NA

NA

Funnel plots of RR against the standard error, and analyzed by the Begg, Egger and Harbor tests

26 studies: 17 75 studies: 63 studies: 7 vs 14 full papers, 12 day, 12 studies 7 abstracts vs 10 day therapy

Number of included studies

13 14 studies: 8 full 21 studies: 17 9 studies studpapers, 6 full papers, 4 abies: 6 abstracts stracts full papers, 7 abstracts

10 studies

Number of studies that included by other metaanalyses but we further excluded

5 studies: 4 abstracts had been published in full or updated (

NA NA (we contracted the authors but could not retrieve the studies

5 studies: 1 was not a real RCT (Lamouliatte 2000) , 4 abstracts had been published in full or updated (Dammann 1997; Katicic 1996; Paoluzi 2001; Vakil 2002a). Dammann 1997;

2 abstracts NA (we contracted the au(Karatapanis thors but could not retrieve the studies they included) 2005; Katicic 1996) , which had been updated by another 2 abstracts


Note: We included 6 studies or arms that excluded by Fuccio 2007 up to Fuccio’s search date: Bhasin 2000 (not recommended dose), Ching 1998 (PUD subgroup, H. py-

393

Table 2. Characters of published meta-analyses that compared different durations of H. pylori eradication regimens, and the comparisons with current meta-analysis (Continued) Habu 1997; Katicic 1996; Lamouliatte 1998), one of them further excluded because not a real RCT ( Lamouliatte 1998) ; 1 full paper only had PP results (Chen 1996a)

they included)

lori assessed one week after PPI), Dammann 2000 (metronidazole used 10 days in 14 days’ group) , Gumurdulu 2004 (antibiotics used >1 months, seems to be a typo), Kiyota 1999 (H. pylori assessed soon after ranitidine), Paoluzi 1998 (the studies included treatment failure subjects but the authors confirmed it was a misinterpretation)

Results of PPI triple therapy: 14 vs 7 7 studies, days Peto OR= 0.62 (95% CI 0.45 to 0.84).

10 studies with 12 arms, RR=0.88 (95% CI 0.83 to 0.93) , RRR=0.12 (95% CI 0.07 to 0.17), NNT=12 (9 to 21)

13 studies (14 arms), (73% vs 78%), RR=1.07 (95% CI 1.03 to 1.12) . Subgroups: amoxicillin-based (11 studies), RR=1. 07 (95% CI 1.03 to 1.12). Metronidazolebased (3 studies) , RR=1.08 (95% CI 0.96 to 1.22)

7 vs 14 80.1% vs 89.5%, OR=2. RR 0.79, 95% For days, 22 (95% CI 1.69 to 2.92) CI 0.71 to 0.89, all PPI: 79.6% P

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Pharmacological regimens for eradication of Helicobacter pylori: an overview of systematic reviews and network meta-analysis.

Hybrid Therapy Regimen for Helicobacter Pylori Eradication.

One week eradication regimen for Helicobacter pylori.

Current Status of Five Different Regimens for Empiric First-Line Helicobacter pylori Eradication in Turkey.

Comparison Between 10- and 14-Day Hybrid Regimens for Helicobacter pylori Eradication: A Randomized Clinical Trial.

A Comparison between Hybrid and Concomitant Regimens for Helicobacter Pylori Eradication: A Randomized Clinical Trial.

Comparison of quadruple and triple Furazolidone containing regimens on eradication of helicobacter pylori.

Serological assessment of Helicobacter pylori eradication.

Functional dyspepsia symptom resolution after Helicobacter pylori eradication with two different regimens.

Are probiotics useful in Helicobacter pylori eradication?

CYP2C19 polymorphism influences Helicobacter pylori eradication.

Helicobacter pylori reinfection 4 years post-eradication.

Recent advances in Helicobacter pylori eradication.

Helicobacter pylori eradication: gastric cancer prevention.

Helicobacter pylori eradication and metachronous gastric cancer.

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Fluoroquinolone-based protocols for eradication of Helicobacter pylori.

Helicobacter pylori Eradication, a Gordian Knot for Idiopathic Thrombocytopenic Purpura?

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Can eradication rate of gastric Helicobacter pylori be improved by killing oral Helicobacter pylori?

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Ten-year trend of the cumulative Helicobacter pylori eradication rate for the 'Japanese eradication strategy'.

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